This application is a divisional of application Ser. No. 10/450,118, which is a U.S. National Stage Application of International Application No. PCT/JP01/10838, filed Dec. 11, 2001.
TECHNICAL FIELD The method of this application relates to analysis of unknown gene function, to a gene function database used for the analysis and to a method constructing the database. More particularly, the invention of this application relates to a novel method for analyzing function of function-unknown gene which is useful as a genetic material for the pharmacogenomics and for the manufacture of various useful proteins by means of genetic engineering and to a gene function database used for the analysis as well as a method for constructing the database.
BACKGROUND ART As a result of the human genome project, all of human gene sequences will be soon elucidated. It is predicted that, in near future, causative genes for all genetic diseases will be made clear. Identification of causative genes for diseases is expected to greatly contribute in correct and simple diagnosis of diseases or in effective preventive treatment and therapy.
However, although many causative genes have been identified already, the greater part thereof has not yet been applied for the development of therapeutic drugs or others. That is because functions of the causative genes (functions of expression products) have not been elucidated yet. For example, even when the relevancy of the causative gene with pathology is made clear using knockout mice, etc., the action mechanism of a genetic product during that process is ambiguous and, therefore, it is not possible to search a compound (a lead compound) affecting a gene product (a target protein) and to develop the drug using such a compound.
Until now, analysis of gene function is greatly dependent upon discretion of researchers, and a lot of labor and expense have been paid for analysis of one gene function. It is predicted that, in future, identification of a gene product relating to an expression product of the causative gene for disease among huge numbers of genetic products will become more and more difficult, and there has been a strong demand for development of a new method for analysis of gene function.
The invention of this application has been achieved under the above-mentioned circumstances, and objects of the invention are to provide a novel method for a simple and correct analysis of function of function-unknown genes, a database for analyzing gene function used for the analysis method and a method of constructing the database.
DISCLOSURE OF INVENTION As an invention for solving the above-mentioned objects, this application provides a method for construction of a gene function database, which comprises:
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- (a) ensuring the viability against a plural number of drugs (D1, D2, D3, . . . Dn) at various concentrations, of transformed eukaryotic cells overexpressing a plural number of function-known genes (g1, g2, g3, . . . gn) and their parental cell lines;
- (b) calculating the ratio of the concentration value of the drug to inhibit the viability of the transformed cell to an extent of 40% (IC40 value) to the IC40 value of the parental cell line;
- (c) calculating the logarithmic values of the ratios of the above (b) for the known genes (g1, g2, g3, . . . gn); and (d) calculating the correlation coefficients among the known genes (g1, g2, g3, . . . gn) for the logarithmic values of the above (c).
In the method for constructing the database, it is a preferred embodiment that “n” of the known genes (gn) is 50 or more, and that “n” of the drugs (Dn) is 40 or more.
This application further provides a gene function database, which is constructed by the above constructing method.
This application furthermore provides a method of analyzing functions of a function-unknown gene (gx) on the basis of DSPA (Drug Sensitivity Pattern Analysis) using the gene function database set forth above, which comprises:
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- (i) measuring the IC40 value for each drug from the viability at various concentrations of a plural number of drugs (D1, D2, D3, . . . Dn) for transformed eukaryotic cells overexpressing the unknown gene (gx),
- (ii) calculating the correlation coefficients between the unknown gene (gx) and known genes (g1, g2, g3, . . . gn) from the IC40 values of the above (i) by the same method as in the calculation of the correlation coefficient among the known genes (g1, g1, g3, . . . gn) of the gene function database, and
- (iii) determining that the function of the known gene showing a significant correlation coefficient to the unknown gene (gx) is related to the function of the unknown gene (gx).
This application still further provides a method for constructing the database according to claim 1, wherein the data of the unknown gene (gx) whose function is determined by the method of analyzing functions is added to database as a data of the function-known gene, and still furthermore provides a gene function database constructed by the constructing method set forth above.
BRIEF DESCRIPTION OF DRAWINGS FIG. 1 is examples of selection of high-expression cells by Western blotting method.
FIG. 2 is an example of calculating the ratio of IC40 values from a curve showing the dependency of concentration of drug on viability. The range of an arrow in the drawing shows log 0.23=−0.64.
FIG. 3 is another example for calculating the ratio of IC40 values from a curve showing the dependency of concentration of drug on viable rate.
FIG. 4 shows graphs where drug-sensitivity ratios of genes having high functional relationship (IkB-SR and IKK-DN) and genes having low functional relationship (IkB-SR and p16) are subjected to a logarithmic plotting.
BEST MODE FOR CARRYING OUT THE INVENTION The gene function database of this application is constructed by the following steps (a) to (d).
Step (a): There are measured the viabilities, against a plural number of drugs (D1, D2, D3, . . . Dn) at various concentrations, of transformed eukaryotic cells overexpressing a plural number of function-known genes (g1, g2, g3, . . . gn) and their parental cell lines.
The function-known genes are those where functions of the expression products thereof have been known already and, with regard to their numbers, not less than 50 or, preferably, not less than 100 genes are used. Full-length cDNA of each of those genes is integrated into an expression vector for eukaryotic cells and the recombinant vector is transfected into eukaryotic cells. With regard to the expression vector, known vectors such as pRc-CMV, pcDNA3 and pMSG may be appropriately used. With regard to the eukaryotic cells, there may be exemplified cell lines such as mouse fibroblast cell NIH3T3 and Ha-ras-NIH3T3 although they are non-limitative. Transfectants may be selected using an appropriate selecting drug depending upon the type of the drug-resistant gene of the vector. All of cell lines into which each of the genes (g1, g2, g3, . . . gn) is introduced are checked for gene expression by Western blotting method or Northern blotting method, and the most highly expressed cell line is selected.
Then, with regard to those gene-introduced cells and the parental cell line thereof, their viabilities to a plural number of drugs at various concentrations are measured. The drugs are physiologically active substances (such as cytokines) or drugs which have been known to affect the viabilities of the parental cell line, and they are other than the object drugs for the drug-resistant gene owned by the vector used for the introduction of the gene. Forty kinds or more of drugs are used.
Cell viabilities can be measured by various known methods, and MTT method is preferred. The MTT method is a method where coloration of formazan which is a metabolite of MTT dye (tetrazolium salt 3-(4,5-dimethylthiasol-2-yl)-2,5-diphenyltetralin bromide) by mitochondrial succinic dehydrogenase of growing cells is measured (J. Immunol. Methods 65: 55-63, 1983; J. Immunol. Methods 116: 151-158, 1989) and, because of its quickness and precision, it has been used as a method for measuring the cell growth.
Step (b): There are calculated the ratios of the concentration value of the drug to inhibit the viabilities of the transformed cell to an extent of 40% (IC40 value) to the IC40 value of the parental cell line. Thus, for example, ratio of the IC40 values can be calculated from the concentration-dependent curve on the viability as shown in FIG. 2 and FIG. 3 prepared in the Examples mentioned later.
Step (c): With regard to all of the known genes (g1, g2, g3, . . . gn), there are calculated the logarithmic values of the ratios calculated in the above step (b). The logarithmic values are inputted, for example, into a list (Table 2) prepared in the Examples mentioned later.
Step (d): There are calculated the correlation coefficients among the known genes (g1, g2, g3, . . . gn) for the logarithmic values of the above step (c). The correlation coefficients thereof (r) can be expressed as shown in the list (Tables 3 to 14) which are prepared in the Examples mentioned later, and can be subjected to a test of significance by t-test.
By the above-mentioned method, there is prepared a gene function database equipped with information how the function-known genes are functionally related to each other. The database is inputted into a computer and used for a method of analyzing gene functions which will be mentioned later.
Now the method of analyzing gene functions provided by this application will be illustrated.
The method of analyzing gene functions of this invention using DSPA is a method where function-unknown gene (gx) is analyzed using the above gene function database and comprises the following steps (i) to (iii).
Step (i): There is measured the IC40 value for each drug from the viabilities at various concentrations of a plural number of drugs (D1, D2, D3, . . . Dn) for transformed eukaryotic cells overexpressing the unknown gene (gx).
Types of the vector for recombination of cDNA of unknown gene (gx), the eukaryotic cells and the drugs and measurement of the viabilities are the same as those in the above step (a) for the construction of the gene function database.
Step (ii): There are calculated the correlation coefficients between the unknown gene (gx) and the known genes (g1, g2, g3, . . . gn) from the IC40 value of the above step (i) by the same method (steps (b) to (d)) as in the calculation of the correlation coefficients among the known genes (g1, g2, g3, . . . gn) of the gene function database.
Step (iii):
There is determined that the function of the known gene showing a significant correlation coefficient to the unknown gene (gx) is related to the function of the unknown gene (gx).
Thus, in the t-test for the calculation of the correlation coefficient “r”, t={r2(n−2)/(1−r2)}1/2 (n: data numbers). Therefore, in case the data for 40 or more kinds of drugs are available, the correlation coefficient “r” is significant when it is not less than 0.4 or not more than −0.4. More preferably, when the case where correlation coefficient “r” is not less than 0.5 or not more than −0.5 is used as a standard, it is possible to clearly specify the relationship among the genes. In the case of each of genes shown in Tables 3 to 14, the gene Ha-ras for example shows a correlation of not less than 0.5 to Ki-ras (r=0.71), N-ras (0.56) and erbB2 (0.53), and shows a correlation of not more than −0.5 to Cip-1 (−0.55), RhoA (−0.55) and C/EBPb (−0.50) whereupon it is noted that Ha-ras is functionally related to those genes. When there is such a high correlation between unknown gene and known gene, it is can be judged that the function of the known gene is related to the function of the unknown gene as well.
Incidentally, the above steps (ii) and (iii) can be quickly processed by a computer. Further, when the data of the function-unknown gene being newly functionally analyzed by the method of analyzing the gene functions are appropriately added to the above-mentioned database, it is now possible to be developed to a database having higher accuracy.
As a result of the method of analyzing gene functions as mentioned above, function of the unknown gene can be quickly decided, and action mechanism of the genetic product can be estimated with a high accuracy. Thus, in most cases, overexpression of gene affects the molecule which is related to the product thereof. The molecule affected as such further affects the surrounding molecules and, as a result, a pathway such as a signal transduction is activated or inactivated. Such a cell shows a different sensitivity to the drugs which act the molecule relating to the pathway. Alternatively, it also shows a different sensitivity to a physiologically active substance acting on the same pathway such as cytokines. On the other hand, it has been confirmed that, in the case of genes where their functional relations have been known already (such as p53 and p21), similar sensitivity to the drugs is noted. It is presumed that there are several decades of main signal transduction pathways and that, even when minor routes accompanied therewith are included, there are about 100 kinds. Accordingly, by constructing a database where result of influence (or result of non-influence) to sensitivity to drugs by overexpression of function-known genes (preferably, 100 kinds or more) made into a pattern using the correlation value for each other followed by comparing the result of the overexpression of function-unknown genes with the database, it is possible to identify the pathway concerning the product of the function-unknown genes. Further, when the pathway is investigated, a direct action mechanism of the genetic product can be elucidated with a high accuracy.
The invention of this application will now be illustrated in more detail and specifically by way of the following Examples, although the invention of this application is not limited to the following Examples.
EXAMPLES 1. Materials With regard to the function-known genes, the genes shown in the left column of Table 2 were used. With regard to the drugs, those shown in Table 1 were dissolved in DMSO to an extent of 100-fold of the maximum concentration for the search of the drugs and used. With regard to the cells, incubated NIH3T3 or ras-NIH3T3 cells were used.
TABLE 1
Tyrosine kinase inhibitors
HMA herbimycin A Src, Abl inhibitor
erbstatin EGFR inhibitor
genistein Tyr kinase, topo II inhibitor
Ser/Thr kinase inhibitors
Staurosporine PKC, cdk, MLCK inhibitor
K252a CaM-kinase inhibitor
H-7 PKA, PKC, PKG inhibitor
GF109203X PKC inhibitor
Y-27632 ROCK inhibitor
olomoucine cdk inhibitor
Phosphatase inhibitors
OA okadaic acid PP1, PP2A inhibitor
cantharidin PP2A inhibitor
Na vanadate sodium vanadate tyrosine phosphatase inhibitor
NaAsO2 sodium arsenite tyrosine phosphatase inhibitor
Anti-cancer drugs
MMC mitomycin C DNA cross-linker
5-FU 5-fluorouracil thymidine synthetase inhibitor
CDDP cisplatin DNA cross-linker
MTX methotrexate DHFR inhibitor
MIT mitoxantrone DNA strand break
ACR aclarubicin DNA intercalator
IFM ifosfamide DNA alkylation
ACD actinomycin D RNA polymerase inhibitor
HU hydroxyurea ribonucleotide reductase inhibitor
6-TG 6-thioguanine purine metabolism inhibitor
CPT camptothecin topoisomerase I inhibitor
PPL pepleomycin DNA strand break
VCR vincristine microtubule depolymerization
Protease inhibitors
ALLN Ac-Leu-Leu-leucinal calpain/proteasome inhibitor
ONO-3403 trypsin inhibitor
ONO-5046 elastase inhibitor
ICEin-III ICE inhibitor-III caspase inhibitor
Others
wortmannin PI3-K inhibitor
manumycin farnesyltransferase inhibitor
cytochalasin D actin polymerization inhibitor
ouabain Na+, K+-ATPase inhibitor
A23187 Ca2+ ionophore
BAPTA-AM Ca2+ chelator
thapsigargin Ca2+-APTase inhibitor
U73122 phospholipase C inhibitor
SnPP heme oxygenase inhibitor
curcumin 5-lipoxygenase & cyclooxygenase inhibitor
forskolin adenylate cyclase activator
IBMX phosphodiesterase inhibitor
CHX cycloheximide protein synthesis inhibitor
SNAP NO donor
resveratrol antioxidant; estrogen-R agonist, COX1 inhibitor
ribonucleotide reductase inhibitor
sulindac COX inhibitor
IMT indomethacin COX1/2 inhibitor, phospholipase A2 inhibitor
NaN3 sodium azide cytochrome a/a3 binding
β-elemene herb medicine
2. Methods (1) Preparation of Cells Overexpressing Genes Full-length cDNA of each function-known genes was incorporated into an expression vector (pRc-CMV, etc.) and transfected into NIH3T3 cells by a common method. Transformed cells were isolated using the resistance to G-418 as an index and the expression of the transfected gene in each cell was investigated by Western blotting method to select a highly expressing line. FIG. 1 shows examples of gene expression by Western blotting method.
(2) Measurement of Cell Viabilities by MTT Method Cell viabilities were measured according to the following procedures.
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- 1) From the 2nd to the 11th rows of a 96-well plate were filled with DMEM (50 μl). The 12th row was filled with 100 μl of DMEM.
- 2) The 1st row was filled with 98 μl of DMEM.
- 3) Drugs (2 μl each) were added into the 1st row.
- 4) Continuous double-dilution was conducted from the 1st to the 9th rows. Fifty μl were taken out from the 9th row and discarded. The plate was preserved in a CO2 incubator.
- 5) Cells (each high-expressing cells and the parental cell line) were detached from the medium using a trypsin solution, suspended in 10% CS-DMEM and transferred to a test tube and cell numbers (cell/ml) were counted.
- 6) The cells were diluted to a concentration of 1×105 cells/ml, and 50 μl of the cell suspension were added to the 1st to the 11th rows of the plate followed by gently stirring.
- 7) The plate was transferred to the CO2 incubator and incubated for 3 to 4 days.
- 8) MTT (5 mg/ml in PBS) (10 μl) was added to the 1st to the 12th rows of the plate and incubated in the CO2 incubator at 37° C. for 4 hours.
- 9) A reaction stop solution (0.04N HCl in isopropanol) (150 μl) was added followed by mixing well and being allowed to stand at room temperature for about 2 hours.
- 10) Coloration of formazan which was a metabolite of the MTT dye was measured using a microplate reader. The measurement wavelength was 574 nm and the reference wavelength was 655 nm. The 10th and the 11th rows of the plate were 100% controls and the 12th row was a 0% control.
(3) Calculation of Logarithmic Values of Ratios of IC40 Values As an index for the sensitivity of highly gene-expressing cells and the parental cell line to various drugs, each of the IC40 values thereof was specified and ratios of the IC40 values were calculated. FIG. 2 and FIG. 3 are the examples where ratios of IC40 values were calculated from a curve showing the dependency on the concentration of the chemical versus the viability. After that, logarithmic values of ratios of IC40 values were calculated from each gene. Table 2 is a part of the list of the logarithmic values.
TABLE 2
Stauro-
GF109203X sporine K252a H-7 HMA Genistein Erbstatin Ouabain 6-TG OA SnPP Vanadate ALLN
Ha-ras −0.39 0.30 0.65 0.23 −0.35 −0.35 0.08 0.32 −0.19 0.11 0.28 −0.33 0.15
Ki-ras −0.40 0.38 0.15 0.28 −0.14 0.00 0.04 0.18 −0.30 0.04 0.18 −0.30 0.11
N-ras 0.24 −0.16 0.30 0.43 0.42 −0.22 0.56 −0.22 0.00 0.14 −0.09 0.17
v-src −0.29 −0.05 −0.22 −0.07 −0.35 −0.60 −0.05 0.00 0.00 0.18 −0.17 0.00 0.10
erbB2 −0.40 0.04 0.15 0.00 −0.55 −0.60 −0.05 0.18 −0.12 −0.19 −0.25 −0.40 −0.05
p53 (wt) 0.62 0.07 0.05 0.00 −0.22 0.26 0.17 0.09 0.32 −0.05 −0.18 0.00 0.18
Cip-1 0.30 0.00 0.00 −0.30 0.16 0.47 −0.15 −0.66 0.00 0.18
p16/INK4A 0.48 −0.22 −0.22 0.08 0.41 0.40 0.51 0.63 0.46 0.06 −0.05 0.11 0.09
Bax 0.22 −0.22 −0.11 0.08 −0.05 0.20 0.27 0.40 0.36 0.00 0.17 0.00 −0.10
Bax 0.27 0.00 0.60 0.00 0.15 0.38 0.04 0.00 −0.05 0.00 0.10 0.32 0.11
TK 0.00 0.46 0.23 −0.55 0.00 0.08 0.05 0.00 −0.17 0.00 0.00 0.16 0.00
m-calpain 0.35 0.00 0.13 0.15 0.00 0.18 0.00 0.05 0.29 −0.08 −0.07 −0.10 0.00
cAMP-PK-CS 0.27 −0.12 −0.04 0.15 0.12 0.00 0.05 0.00 0.14 0.08 0.02 0.00 0.20
calpastatin 0.04 0.1 −0.14 −0.14 0.127 −0.2 −0.3 −0.25 −0.04 0.486 0.00 0.10
CP-antisense 0.00 −0.15 0.00 0.00 −0.10 0.00 0.06 0.28 0.14 0.13 0.10 0.04 0.00
DAN 0.65 0.48 −0.46 0.18 −0.05 0.20 0.20 0.74 0.64 0.04 −0.49 0.30 0.00
Regucalcin −0.05 −0.09 −0.34 −0.02 −0.20 0.00 0.00 −0.12 0.20 −0.10 0.32 0.00 0.00
cystatin alpha 0.60 0.30 −0.10 0.60 −0.12 0.28 0.08 1.28 0.60 0.08 0.00 0.08 0.07
cystatin E 0.27 0.40 −0.19 −0.05 0.00 0.21 −0.06 0.49 0.00 −0.52 0.11 0.20 0.19
caspase-1 0.23 0.22 0.04 0.00 0.00 −0.12 −0.22 1.26 0.34 0.00 −0.15 −0.11 −0.04
caspase-3 0.82 0.00 0.15 −0.15 0.08 0.04 −0.10 0.65 1.16 0.00 −0.40 0.14 −0.09
caspase-2 0.92 0.18 0.37 0.28 0.10 0.30 −0.07 −0.05 0.18 0.06 −0.33 0.40 −0.04
RhoA 0.24 0.15 0.10 0.35 0.13 0.31 0.14 0.15 0.69 0.00 0.14 0.28 0.00
RhoA-DN 0.14 0.28 0.22 −0.10 0.00 −0.02 0.45 0.41 0.00 0.08 −0.12 0.00
PDGF-R 0.00 0.24 0.10 −0.07 0.19 0.32 0.34 0.22 0.16 −0.07 0.22 0.22
PDGF-R-Del 0.91 0.28 0.10 0.28 0.00 0.33 0.00 0.19 0.51 0.21 0.08 0.00 0.10
Glucocorticoid-R 0.27 −0.28 0.13 0.08 −0.11 0.02 0.06 0.04 0.09 0.06 0.00 0.03 0.12
STAT1 0.41 0.00 0.15 0.08 −0.05 0.10 0.04 0.04 0.20 0.14 0.08 0.00 0.17
CBP8 0.16 0.19 0.28 −0.06 0.09 0.10 0.14 0.58 0.38 0.12 0.56 0.03 0.11
PKCalpha-KN 0.22 0.00 0.16 0.14 0.09 0.16 0.00 0.26 0.09 −0.14 0.23 0.11
PKCalpha-KN 0.62 −0.10 0.02 0.20 −0.10 0.24 0.00 0.06 0.38 0.00 0.00 0.08 −0.01
PKCepsilon-KN −0.17 −0.07 0.00 −0.21 −0.11 0.00 −0.12 −0.15 0.00 0.00 0.27 0.09 0.07
PKCepsilon-KN 0.32 −0.10 −0.09 0.16 0.09 0.19 0.00 −0.12 0.00 0.00 0.24 0.18 0.19
TPA 0.09 −0.12 −0.13 0.00 −0.07 −0.09 0.00 −0.08 0.00 0.12 −0.20 −0.03 −0.09
(PKC downreg
ERK-DN 0.48 0.06 0.05 0.14 0.00 0.00 0.13 0.48 0.32 0.00 0.00 0.00 0.00
JNK-DN 0.58 0.14 −0.28 0.09 −0.14 −0.10 0.11 −0.08 0.00 −0.07 −0.11 −0.17 −0.24
p38-DN 0.58 −0.05 −0.15 0.10 −0.05 0.00 0.06 0.41 0.33 0.12 0.10 −0.04 0.04
HSP40 −0.07 0.30 0.07 0.15 0.00 0.00 0.00 0.00 0.50 −0.02 0.28 −0.03 0.18
HSP90 0.22 0.56 −0.03 0.40 0.41 0.26 0.92 0.57 0.07 0.02 0.16
CaMKIIa 0.04 0.12 0.04 0.00 0.00 −0.15 0.14 0.23 0.00 0.00 0.24 −0.13 0.00
CaMKIIa-Active −0.04 0.10 0.13 0.51 0.23 0.21 0.60 0.62 0.14 0.30 0.01 0.20
HNF1 0.345 0 −0.207 0.149 0.161 0.234 0.391 0.103 0.46 0 0.138 0.046 0.16
HNF3b 0.21 0.00 −0.21 −0.11 −0.18 −0.21 −0.03 −0.23 0.03 0.08 0.24 0.22 0.28
HNF4 0.40 0.04 −0.22 0.09 −0.08 −0.15 2.00 −0.08 0.00 0.08 0.46 −0.03 −0.15
coup 0.46 0.08 0.00 0.28 0.42 0.44 0.33 0.49 0.45 0.00 0.51 −0.10 0.06
C/EBPa 0.00 0.00 −0.48 −0.35 0.00 −0.43 0.11 0.00 0.00 0.12 −0.00 −0.02 0.00
C/EBPb −0.23 0.25 0.00 0.45 0.19 0.48 0.00 0.30 0.21 −0.50 0.31
p33/ING1 −0.28 0.62 0.28 0.00 0.38 0.78 0.11 0.10 0.46 0.11 −0.23 −0.30 0.08
T.Tn −0.10 0.00 0.00 0.00 0.00 −0.25 0.48 0.28 0.00 −0.16 0.00 0.46 0.48
Thapsi- Wort- Manu-
3403 5046 ICEin-3 Forskolin U73122 gargin BAPTA-AM mannin mycin A23187 NaAsO2 CHX b-elemene
Ha-ras −0.22 0.00 0.32 0.26 −0.19 0.00 −0.20 0.34 −0.30 −0.28 0.04 −0.19 −0.26
Ki-ras −0.30 0.51 0.30 0.36 −0.60 −0.05 −0.15 0.34 −0.24 0.06 0.08 −0.43 −0.10
N-ras −0.17 0.23 0.38 0.54 −0.54 0.08 0.00 0.14 −0.09 0.20 −0.19 −0.42 0.07
v-src −0.05 0.51 −0.14 −0.46 −0.59 0.32 −0.22 0.08 0.00 −0.19 0.11 −0.32 −0.35
erbB2 −0.15 0.80 0.18 0.28 −0.96 0.11 −0.40 0.16 −0.05 −0.07 −0.15 −0.64 −0.46
p53 (wt) 0.04 0.23 0.98 0.11 −0.05 0.00 0.40 0.12 0.30 0.20 0.85 0.00
Cip-1 0.04 −0.14 0.08 0.08 0.04 0.00 0.12 0.04 0.30 1.77 0.00
p16/INK4A 0.29 0.22 0.15 0.70 0.28 −0.64 0.20 0.30 0.08 0.00 0.16 0.04 0.12
Bax 0.12 −0.07 −0.12 0.00 0.00 −0.21 0.15 0.14 −0.07 0.00 −0.10 −0.08 0.14
Bax 0.00 0.00 0.00 −0.26 0.00 0.20 0.00 0.10 0.06 −0.09 0.34 0.00 0.00
TK 0.09 −0.24 −0.15 0.56 0.00 0.06 0.00 0.00 0.00 0.00 0.18 −0.13 −0.14
m-calpain 0.00 −0.04 −0.06 0.25 −0.14 0.05 0.00 0.18 0.05 0.26 −0.16 0.22 0.00
cAMP-PK-CS 0.00 0.00 0.00 0.51 −0.18 0.05 −0.10 −0.07 0.08 −0.08 0.07 0.23 −0.10
calpastatin 0.00 −0.1 −0.088 −0.09 −0.313 0.046 0 −0.14 0.02 −0.12 0 0.31 0.18
CP-antisense 0.00 −0.06 −0.19 −0.05 −0.10 −0.30 0.06 −0.12 0.00 −0.36 0.02 0.00 0.00
DAN 0.08 0.26 0.00 0.88 0.36 0.18 0.70 0.52 0.00 0.40 −0.15 0.72 0.04
Regucalcin 0.12 −0.38 0.00 −0.10 −0.66 0.20 −0.39 −0.28 0.04 0.03 0.03 0.08 −0.09
cystatin alpha −0.10 0.32 0.72 0.04 0.04 0.34 0.45 −0.19 0.26 −0.05 0.34 0.08
cystatin E −0.15 0.36 0.07 0.29 −0.07 0.00 −0.02 0.00 0.00 0.22 0.15 0.00 0.07
caspase-1 −0.06 0.40 0.11 0.34 0.53 −0.30 0.60 0.20 −0.06 −0.22 −0.21 −0.05 0.11
caspase-3 0.00 0.40 0.13 1.12 0.53 −0.17 0.60 0.45 0.04 0.28 0.11 0.10 0.28
caspase-2 0.15 0.51 0.04 −0.34 −0.02 −0.07 0.23 0.52 0.08 0.48 0.18 0.74 0.26
RhoA 0.00 0.11 0.19 0.47 0.12 0.26 0.00 0.24 −0.04 0.26 0.07 0.14 0.00
RhoA-DN 0.22 0.00 0.00 −0.36 −0.35 0.06 0.09 0.00 −0.13 0.03 0.00 0.22
PDGF-R 0.00 0.36 0.20 0.16 −0.11 0.29 0.29 0.00 0.17 0.31 0.14 0.51 0.00
PDGF-R-Del 0.22 −0.07 0.00 0.51 0.00 0.24 0.31 0.07 0.09 0.15 0.00 0.39 0.16
Glucocorticoid-R 0.10 0.00 0.00 0.33 0.05 0.20 0.10 0.09 0.09 0.28 0.16 0.09 0.00
STAT1 0.16 0.05 0.09 0.51 0.18 0.30 0.10 0.00 0.00 0.31 0.16 0.00 0.05
CBP8 0.08 0.12 0.18 0.40 0.18 0.12 0.00 0.14 0.09 0.22 0.21 0.00 0.06
PKCalpha-KN 0.04 0.10 0.12 −0.47 −0.33 0.10 0.43 0.41 0.00 0.22 0.16 0.30 0.07
PKCalpha-KN 0.11 −0.05 0.33 0.00 −0.97 0.12 −0.42 −0.06 0.16 −0.05 0.22 0.29 −0.07
PKCepsilon-KN 0.04 −0.21 −0.21 0.00 −0.21 0.09 0.00 −0.15 −0.11 −0.28 −0.07 0.06 0.00
PKCepsilon-KN 0.00 0.00 0.33 0.00 −0.38 0.20 0.00 −0.28 0.16 0.15 0.35 0.20 −0.23
TPA (PKC downr 0.10 −0.10 −0.09 −0.17 −0.12 −0.23 −0.03 0.00 0.03 −0.22 −0.20 0.00 0.00
ERK-DN 0.10 0.00 0.00 0.08 0.00 −0.15 0.12 −0.11 −0.05 0.00 0.16 0.08 0.33
JNK-DN 0.22 −0.09 0.00 −0.22 −0.07 0.24 0.06 −0.09 −0.05 −0.08 −0.07 0.00 −0.04
p38-DN 0.14 −0.04 −0.11 −0.46 0.00 0.02 0.00 −0.18 0.00 −0.12 0.00 0.04 0.05
HSP40 0.17 −0.15 0.11 −0.39 −0.20 0.18 0.05 −0.07 −0.06 −0.16 −0.02 0.00 0.02
HSP90 0.36 0.52 0.22 0.94 0.18 0.09 0.60 0.18 −0.13 0.28 0.10 0.07 0.05
CaMKIIa 0.00 0.00 0.00 0.00 −0.05 0.09 −0.12 −0.15 0.00 0.00 0.00 0.04 0.16
CaMKIIa-Active 0.22 0.35 0.22 0.43 0.00 0.03 0.18 0.18 0.03 0.18 0.02 −0.09
HNF1 0.14 0.05 0.20 1.15 0.07 0.16 0.20 0.16 0.06 0.35 −0.14 0.38 0.02
HNF3b 0.22 −0.25 −0.09 0.00 −0.31 0.24 −0.07 0.24 −0.06 −0.16 0.00 0.07 −0.07
HNF4 −0.09 0.00 0.00 0.00 0.00 0.00 −0.10 0.14 0.00 0.19 0.00 0.22 0.33
coup 0.11 −0.04 −0.11 0.78 0.00 −0.30 0.09 0.10 0.09 −0.12 −0.19 0.12 0.52
C/EBPa −0.41 0.00 −0.46 0.00 0.00 −0.09 −0.62 0.00 0.00 0.00 −0.40 0.00 0.00
C/EBPb 0.36 0.17 0.35 0.93 0.10 0.29 0.81 0.34 0.47 0.25 0.41 0.37 0.50
p33/ING1 0.00 −0.25 −0.15 0.63 0.28 0.49 0.00 0.00 0.18 0.26 −0.07 −0.30 −0.14
T.Tn 0.00 0.00 0.30 0.53 −0.26 0.32 0.11 0.36 0.28 −0.22 −0.05 0.00 −0.14
indicates data missing or illegible when filed
(4) Calculation of Correlation Coefficients by Logarithmic Values In the list of the logarithmic values shown in Table 2, calculation of correlation coefficients by t-test was carried out in each line. FIG. 4 shows graphs where sensitivity ratios of IkB-SR and IKK-DN- and p16-introduced cells to chemicals were logarithmically plotted, and, between IkB and IKK which were functionally correlated, there was a high correlation (r=0.75) while, between IkB and p16 which were not related, the correlation coefficient was 0.09 with no significance. In Tables 3 to 14, the list of all correlation coefficients is shown by dividing into 12.
TABLE 3
Ha-ras Ki-ras N-ras v-src erbB2 abl Ras-N-17 Rb p53(wt) Cip-1 p16/INK4A
Ha-ras 1.00
Ki-ras 0.71 1.00
N-ras 0.56 0.56 1.00
v-src 0.36 0.61 0.08 1.00
erbB2 0.53 0.76 0.35 0.64 1.00
abl −0.16 −0.09 −0.05 −0.17 −0.07 1.00
Ras-N-17 0.11 −0.06 0.12 −0.24 −0.27 0.51 1.00
Rb 0.02 0.06 −0.15 −0.15 −0.02 −0.16 −0.01 1.00
p53 (wt) −0.29 −0.30 −0.34 −0.44 −0.17 0.25 0.30 0.18 1.00
Cip-1 −0.55 −0.37 −0.37 −0.30 −0.31 0.19 0.18 −0.12 0.57 1.00
p16/INK4A −0.36 −0.21 −0.18 −0.26 −0.17 0.18 0.06 −0.04 0.41 0.22 1.00
HSP40 −0.14 −0.13 −0.33 0.01 −0.01 0.03 −0.16 0.45 0.00 0.17 −0.20
HSP90 −0.23 −0.10 −0.32 −0.17 0.00 0.32 −0.01 0.43 0.42 0.15 0.46
Hsdj −0.33 −0.05 −0.18 −0.11 −0.01 0.39 0.19 0.19 0.16 0.34 −0.04
DnaJ-61 −0.15 −0.05 0.05 −0.24 0.03 0.19 0.10 0.21 0.30 −0.05 0.17
Bax (N) −0.36 −0.35 −0.01 −0.34 −0.27 0.09 −0.22 −0.10 0.08 0.25 0.10
Bax (F) −0.20 0.00 −0.11 0.02 −0.06 −0.07 −0.10 0.11 0.08 0.18 0.56
IkB-SR −0.24 −0.28 −0.12 −0.39 −0.28 −0.05 0.16 0.18 0.52 0.44 0.09
IKK-DN −0.58 −0.49 −0.35 −0.48 −0.34 0.18 0.03 0.12 0.45 0.62 0.16
PDGF-R −0.14 0.16 0.18 0.30 0.13 0.35 0.13 −0.20 0.11 0.26 −0.06
PDGF-R-Del −0.38 −0.16 −0.37 −0.19 −0.17 0.19 0.14 0.34 0.45 0.43 0.38
Glucocorticoid-R 0.07 −0.08 0.06 −0.19 −0.04 −0.02 −0.05 −0.06 0.17 0.04 0.10
RhoA −0.10 −0.04 0.11 −0.17 −0.07 0.17 0.07 0.16 0.33 0.10 0.18
RhoA-DN −0.55 −0.35 −0.47 −0.22 −0.16 0.10 −0.05 0.26 0.29 0.53 0.23
CaMKIIa 0.34 0.05 0.15 −0.10 0.06 −0.32 −0.03 0.29 −0.16 −0.23 −0.16
CaMKIIa-Active −0.08 0.12 0.14 −0.06 0.15 −0.10 −0.18 0.23 0.03 0.01 0.41
PKCalpha-KN −0.12 −0.13 −0.11 0.13 −0.09 0.11 0.04 −0.10 −0.02 0.12 0.01
PKCalpha-KN −0.07 0.10 0.05 0.16 0.32 0.08 0.03 0.19 0.35 0.31 0.03
PKCepsilon-KN −0.33 −0.41 −0.36 −0.16 −0.28 0.10 −0.17 0.23 0.21 −0.05 0.18
PKCepsilon-KN −0.09 0.12 0.19 0.22 0.16 −0.06 −0.16 −0.06 0.06 0.11 −0.15
TPA (PKC-) −0.05 −0.20 −0.23 −0.06 −0.09 0.20 0.06 −0.01 0.18 0.08 0.12
Akt-DN 0.05 0.02 0.11 0.10 0.09 0.19 0.40 −0.15 0.36 0.17 −0.03
ERK-DN −0.40 −0.34 −0.51 −0.23 −0.22 0.14 0.15 0.25 0.45 0.39 0.50
JNK-DN −0.21 −0.20 −0.28 −0.03 −0.16 0.05 0.23 0.02 0.21 0.37 0.02
p38-DN −0.30 −0.30 −0.35 −0.09 −0.19 −0.06 0.08 0.13 0.28 0.46 0.18
cAMP-PK-CS 0.08 0.19 −0.02 0.17 0.23 0.14 −0.29 0.18 0.17 −0.06 0.20
HSP40 HSP90 Hsdj DnaJ-61 Bax (N) Bax (F) IkB-TDN IKK-DN
Ha-ras
Ki-ras
N-ras
v-src
erbB2
abl
Ras-N-17
Rb
p53 (wt)
Cip-1
p16/INK4A
HSP40 1.00
HSP90 0.21 1.00
Hsdj 0.34 0.33 1.00
DnaJ-61 −0.05 0.26 0.40 1.00
Bax (N) 0.21 0.09 0.15 −0.06 1.00
Bax (F) 0.17 0.22 0.01 −0.17 0.19 1.00
IkB-SR 0.04 0.23 0.29 0.13 0.12 0.09 1.00
IKK-DN 0.25 0.28 0.41 0.16 0.39 0.16 0.75 1.00
PDGF-R −0.02 0.32 0.10 0.05 0.02 −0.06 0.11 0.16
PDGF-R-Del 0.11 0.62 0.26 0.30 0.02 0.24 0.24 0.44
Glucocorticoid-R −0.25 0.32 0.00 0.26 0.14 −0.03 0.14 0.06
RhoA 0.25 0.43 0.09 0.16 0.38 0.26 0.25 0.17
RhoA-DN 0.51 0.54 0.50 0.16 0.32 0.24 0.32 0.63
CaMKIIa 0.08 −0.01 −0.10 0.13 −0.20 −0.04 0.23 0.10
CaMKIIa-Active 0.04 0.67 0.16 0.14 −0.17 0.24 0.10 0.07
PKCalpha-KN 0.29 0.08 0.06 −0.27 0.44 0.27 −0.04 0.08
PKCalpha-KN 0.36 0.00 0.13 0.12 0.18 0.13 0.05 0.25
PKCepsilon-KN 0.30 0.27 −0.08 0.05 0.48 0.15 0.17 0.32
PKCepsilon-KN 0.13 −0.25 0.00 0.21 0.18 −0.13 −0.19 −0.10
TPA (PKC-) 0.16 0.15 0.10 −0.13 −0.02 0.04 −0.04 0.13
Akt-DN −0.04 −0.05 0.19 0.18 −0.23 −0.05 0.37 0.02
ERK-DN 0.27 0.66 0.24 0.22 0.08 0.38 0.22 0.40
JNK-DN 0.21 0.09 0.14 −0.06 0.02 0.16 0.19 0.31
p38-DN 0.48 0.22 0.07 −0.10 0.10 0.42 0.23 0.40
cAMP-PK-CS 0.12 0.29 0.04 0.13 0.06 0.20 −0.10 −0.07
TABLE 4
Ha-ras Ki-ras N-ras v-src erbB2 abi Ras-N-17 Rb p53(wt) Cip-1 p16/INK4A
14-3-3zWT −0.16 −0.23 −0.30 −0.06 −0.02 −0.12 −0.03 0.34 0.21 −0.11 −0.02
TK 0.28 0.13 0.25 −0.10 0.08 0.11 0.26 0.16 0.03 −0.14 −0.19
caspase-1 0.16 0.03 0.20 −0.13 0.05 0.05 0.18 −0.13 0.05 −0.04 0.28
caspase-3 −0.23 −0.30 −0.23 −0.34 −0.14 0.24 0.19 0.07 0.52 0.18 0.52
caspase-2 −0.45 −0.36 −0.43 −0.18 −0.26 0.12 0.25 −0.03 0.36 0.47 0.38
cystatin alpha 0.12 0.17 0.45 −0.07 0.27 0.13 0.24 0.04 0.39 0.15 0.42
cystatin E −0.13 −0.02 0.06 −0.16 0.02 0.14 0.33 0.20 0.51 0.25 0.28
u-calpain −0.31 −0.27 −0.13 −0.39 −0.23 0.00 0.27 0.13 0.49 0.67 0.07
m-calpain −0.30 −0.18 −0.05 −0.35 −0.10 0.22 −0.05 0.16 0.41 0.27 0.14
calpain 30K (N) 0.10 0.30 0.07 0.68 0.27 0.17 0.03 −0.15 −0.31 0.09 −0.54
calpain 30K (F) −0.15 −0.14 −0.08 −0.19 −0.03 0.02 0.17 0.26 0.29 0.30 0.00
calpastatin 0.35 0.30 0.38 0.14 0.09 −0.31 0.00 0.22 −0.36 −0.28 −0.44
CP-antisense −0.20 −0.17 −0.45 −0.04 −0.08 0.12 0.11 0.31 0.35 0.17 0.44
BH −0.17 −0.27 −0.06 −0.37 −0.33 −0.29 0.03 0.11 0.19 0.29 0.01
DAN −0.45 −0.45 −0.37 −0.33 −0.24 0.27 0.24 0.13 0.44 0.35 0.46
Regucalcin −0.22 −0.12 −0.02 −0.15 −0.05 −0.10 −0.05 0.26 0.32 0.39 0.02
CathL-mut −0.03 −0.14 −0.16 −0.09 −0.24 −0.36 −0.17 0.51 0.00 −0.20 −0.09
STAT1 0.13 0.01 0.09 −0.18 0.00 0.06 0.02 0.12 0.29 0.01 0.05
CBP −0.25 −0.21 −0.32 −0.30 −0.07 −0.14 −0.18 0.40 0.28 0.04 0.43
P/CAF −0.25 −0.18 −0.08 −0.40 −0.08 0.60 0.41 0.16 0.24 0.35 −0.02
HNF1 −0.05 −0.12 −0.01 −0.34 −0.05 0.15 0.20 0.26 0.60 0.07 0.34
HNF3b −0.13 −0.27 −0.19 0.02 −0.11 −0.09 0.09 0.24 0.24 0.09 −0.03
HNF4 0.06 −0.04 −0.18 0.00 −0.01 −0.18 −0.03 −0.03 0.08 −0.06 0.14
coup −0.25 −0.12 −0.17 −0.40 −0.18 0.06 0.13 0.57 0.52 0.19 0.54
C/EBPa −0.13 −0.04 −0.09 −0.07 0.16 0.26 0.21 0.19 0.26 0.30 0.23
C/EBPb −0.50 −0.25 −0.50 −0.04 −0.08 0.27 0.00 0.08 0.45 0.37 0.25
per-1 −0.07 −0.18 −0.19 0.24 0.03 −0.03 0.24 −0.17 0.16 0.37 −0.10
p33/ING1 −0.23 −0.03 −0.15 −0.21 0.04 0.29 −0.11 0.41 0.14 0.17 0.07
T.Tn 0.47 0.42 0.35 0.27 0.37 −0.13 0.06 −0.08 −0.21 −0.20 −0.22
CD44/H-CAM −0.15 0.04 −0.26 0.15 0.09 −0.01 −0.31 0.34 −0.02 0.01 −0.18
CD44/3E −0.22 −0.13 −0.39 0.03 −0.10 0.09 −0.05 −0.03 −0.05 0.15 −0.06
CD44/3s −0.13 −0.11 −0.52 −0.03 −0.11 0.18 0.00 0.25 0.06 0.12 −0.13
Jagged-1 0.16 0.04 0.05 0.01 −0.14 −0.48 −0.17 0.34 −0.17 −0.12 −0.05
p94-WT −0.37 −0.26 −0.26 −0.32 −0.25 −0.10 0.00 0.34 0.27 0.11 0.04
p94-mut −0.23 −0.07 0.02 0.03 −0.14 −0.01 0.05 −0.02 0.04 −0.01 −0.10
E2F-High −0.33 −0.34 −0.10 −0.32 −0.27 −0.01 0.06 0.05 0.42 0.34 0.00
HSP40 HSP90 Hsdj DnaJ-61 Bax (N) Bax (F) IkB-TDN IKK-DN
14-3-3zWT 0.28 0.14 0.19 0.13 −0.01 0.02 0.23 0.26
TK −0.21 −0.06 −0.04 −0.12 −0.12 −0.20 0.16 −0.03
caspase-1 −0.14 0.37 −0.17 0.10 −0.16 0.05 −0.11 −0.10
caspase-3 0.03 0.63 0.06 0.27 0.15 0.31 0.09 0.20
caspase-2 0.08 0.19 0.20 −0.07 0.35 0.38 0.09 0.36
cystatin alpha −0.02 0.51 0.04 0.32 −0.03 0.49 0.12 0.10
cystatin E 0.08 0.55 0.15 0.19 0.04 0.06 0.37 0.24
u-calpain 0.21 0.18 0.40 0.28 0.07 0.14 0.53 0.56
m-calpain 0.25 0.30 0.26 0.25 0.38 0.19 0.23 0.41
calpain 30K (N) 0.17 −0.58 0.36 −0.24 0.17 −0.56 −0.21 −0.16
calpain 30K (F) 0.17 0.28 0.44 0.14 −0.06 −0.05 0.49 0.39
calpastatin 0.00 −0.57 −0.15 −0.01 −0.01 −0.10 −0.06 −0.20
CP-antisense 0.38 0.51 0.11 0.20 0.11 0.38 0.11 0.21
BH 0.02 0.02 0.11 −0.04 0.14 0.06 0.72 0.57
DAN 0.21 0.43 0.28 0.20 0.24 0.48 0.15 0.38
Regucalcin 0.36 −0.08 0.20 0.20 0.13 0.08 0.39 0.37
CathL-mut 0.19 −0.09 −0.23 −0.22 0.20 0.06 0.16 0.11
STAT1 −0.12 0.41 0.03 0.21 −0.01 −0.04 0.19 0.01
CBP 0.10 0.70 0.07 0.32 0.08 0.10 0.26 0.34
P/CAF 0.13 0.14 0.51 0.18 0.12 −0.21 0.15 0.43
HNF1 −0.14 0.30 −0.01 0.43 −0.34 0.07 0.36 0.14
HNF3b 0.32 −0.10 −0.05 −0.09 0.19 0.05 0.27 0.16
HNF4 −0.09 −0.12 0.01 0.17 −0.22 0.17 0.20 0.16
coup 0.17 0.62 0.21 0.30 −0.06 0.43 0.42 0.38
C/EBPa 0.16 0.36 0.36 0.21 0.02 0.22 0.02 0.20
C/EBPb 0.03 0.53 0.33 0.16 −0.05 0.06 0.16 0.28
per-1 0.27 −0.14 0.06 −0.25 0.05 0.04 0.06 0.07
p33/ING1 0.18 0.34 0.26 0.21 −0.02 −0.02 −0.05 0.21
T.Tn −0.14 −0.19 −0.12 −0.08 −0.37 −0.05 −0.01 −0.24
CD44/H-CAM 0.37 0.25 0.40 0.23 0.11 0.07 −0.06 0.03
CD44/3E −0.03 0.13 0.20 0.08 −0.16 −0.22 0.04 0.14
CD44/3s 0.16 0.08 0.22 0.00 −0.14 −0.02 0.25 0.26
Jagged-1 0.06 0.23 −0.25 −0.16 −0.04 0.11 0.00 −0.09
p94-WT 0.12 0.13 0.24 0.11 −0.02 0.00 0.28 0.37
p94-mut −0.18 −0.22 0.19 0.08 0.01 −0.05 0.17 0.12
E2F-High 0.03 −0.12 0.13 0.14 −0.02 −0.09 0.60 0.47
TABLE 5
Ha-ras Ki-ras N-ras v-src erbB2 abl Ras-N-17 Rb p53(wt) Cip-1 p16/INK4A
E2F-Low 0.07 −0.11 0.06 −0.24 −0.08 −0.17 0.01 0.21 0.29 −0.17 0.04
FBRCA1-13 −0.02 −0.15 −0.15 0.03 −0.11 −0.08 −0.09 0.01 −0.25 −0.13 −0.13
FMDM2hwt-6 0.10 0.07 0.13 0.23 −0.03 −0.48 −0.18 −0.01 −0.50 −0.10 −0.35
p27-3 −0.17 −0.36 −0.31 −0.47 −0.41 −0.29 −0.01 0.50 0.21 −0.16 0.17
CAPN10-10 −0.02 0.05 0.01 −0.17 0.12 0.21 0.21 0.18 0.56 0.12 0.23
c-myc-1 −0.17 −0.26 −0.22 −0.30 −0.26 −0.16 0.10 0.15 0.51 0.16 0.21
MSSP-10 −0.02 −0.14 0.17 −0.21 −0.18 −0.47 −0.25 0.23 −0.33 −0.26 −0.19
MM1 −0.41 −0.23 −0.30 −0.28 −0.14 0.30 0.08 0.14 0.48 0.30 0.26
AMY1 0.06 0.03 0.03 −0.28 0.05 0.37 0.15 0.33 0.44 −0.07 0.24
Max −0.04 −0.16 −0.08 −0.29 −0.15 0.27 0.00 0.32 0.21 −0.06 0.19
MDM2-hmut −0.33 −0.32 −0.37 −0.31 −0.21 0.24 0.21 0.27 0.62 0.39 0.45
MDM2-mWT 0.04 0.02 −0.05 −0.02 0.02 0.19 0.26 0.15 0.48 0.04 0.33
TERT-WT 0.22 0.20 −0.01 0.15 −0.02 0.18 −0.02 −0.08 0.04 −0.08 −0.06
TERT-DN −0.32 −0.13 −0.14 −0.17 0.01 0.54 0.23 −0.02 0.44 0.36 0.34
PTEN-WT −0.07 −0.11 0.01 −0.31 −0.07 0.32 0.12 −0.16 0.22 0.03 0.21
PTEN-A3 −0.12 −0.24 0.07 −0.16 0.03 0.27 −0.05 −0.25 −0.07 −0.20 0.15
PTEN-G129R 0.15 0.00 0.13 −0.27 0.08 0.29 0.37 0.09 0.41 −0.12 0.18
Bcl-2 −0.26 −0.30 −0.33 −0.24 −0.30 0.27 0.06 0.26 0.12 0.15 0.21
per2 −0.11 −0.06 0.06 −0.31 −0.05 0.34 0.20 0.14 0.35 0.23 0.10
per3 0.17 0.12 0.22 −0.17 0.09 0.11 0.08 0.14 0.16 0.03 −0.11
Cyclin D1-11 0.15 0.10 0.21 0.04 0.04 −0.05 −0.24 0.01 −0.37 −0.19 −0.28
STAT2-4 0.07 0.05 0.06 −0.07 −0.13 −0.41 −0.42 0.19 −0.15 −0.18 −0.01
TSC1-4 −0.27 −0.41 −0.36 −0.37 −0.27 0.09 −0.04 0.27 0.30 0.20 0.05
Bad-22 −0.11 0.02 −0.05 −0.10 0.05 −0.10 0.01 0.33 0.35 0.36 −0.15
FAPP-4 0.14 0.17 0.20 −0.05 −0.08 −0.11 0.04 0.19 −0.10 −0.15 −0.26
FHO-6 −0.06 −0.07 0.01 −0.14 −0.12 −0.08 0.03 0.32 0.01 0.01 −0.03
F25 + lactacystin −0.15 −0.10 −0.21 −0.22 −0.05 0.00 0.09 0.40 0.29 0.11 0.20
F25 + ONO5046 −0.15 −0.18 −0.27 −0.08 −0.21 −0.49 −0.23 0.41 −0.08 0.08 −0.04
F25 + CA-074 −0.01 0.03 −0.13 −0.07 −0.09 −0.46 −0.34 0.47 −0.08 −0.10 −0.15
F25 + PQQ 0.08 0.05 −0.01 −0.03 −0.15 −0.59 −0.37 0.37 −0.30 −0.27 −0.16
F25 + PD98059 0.02 0.17 0.12 0.10 0.10 −0.03 0.10 0.01 0.27 −0.02 0.19
F25 + ALLN −0.24 −0.08 −0.13 0.05 0.01 0.17 0.15 −0.14 0.26 0.23 0.26
F25 + ONO3403 −0.47 −0.52 −0.55 −0.36 −0.25 0.08 −0.09 0.21 0.35 0.22 0.28
F25 + Y27632 −0.11 −0.26 −0.23 −0.30 0.01 −0.04 0.10 0.30 0.56 0.18 0.27
HSP40 HSP90 Hsdj DnaJ-61 Bax (N) Bax (F) IkB-TDN IKK-DN
E2F-Low −0.12 −0.09 −0.14 0.39 −0.20 −0.23 0.33 0.03
FBRCA1-13 0.27 −0.14 0.02 0.21 −0.12 −0.14 −0.20 −0.09
FMDM2hwt-6 0.21 −0.43 −0.10 −0.10 −0.03 −0.09 −0.18 −0.19
p27-3 0.18 0.41 −0.01 0.23 0.00 0.15 0.24 0.15
CAPN10-10 −0.26 0.45 0.13 0.28 −0.20 0.04 0.21 0.06
c-myc-1 −0.03 0.37 −0.06 0.04 −0.07 0.13 0.24 0.10
MSSP-10 0.19 −0.19 −0.10 0.14 0.04 −0.06 0.11 0.01
MM1 0.27 0.55 0.39 0.25 0.04 0.15 0.21 0.28
AMY1 −0.08 0.32 0.18 0.48 0.08 −0.03 0.05 0.13
Max 0.10 0.29 0.08 0.22 0.02 0.01 −0.11 −0.03
MDM2-hmut 0.20 0.54 0.38 0.27 0.01 0.28 0.33 0.33
MDM2-mWT 0.01 0.24 0.04 0.20 −0.29 0.03 0.19 −0.04
TERT-WT −0.02 −0.19 −0.18 −0.11 −0.10 0.02 −0.13 −0.15
TERT-DN −0.15 0.53 0.34 0.25 −0.06 0.07 0.12 0.24
PTEN-WT −0.16 0.24 0.06 0.39 −0.01 0.10 0.03 0.11
PTEN-A3 −0.01 −0.04 −0.07 0.12 0.25 −0.12 −0.31 −0.04
PTEN-G129R −0.25 0.16 0.04 0.51 −0.30 −0.15 0.10 −0.11
Bcl-2 0.23 0.22 0.08 −0.09 0.13 0.12 −0.07 0.16
per2 −0.09 0.29 0.34 0.18 0.28 −0.04 0.14 0.29
per3 0.00 0.14 0.24 0.10 0.17 −0.02 0.16 0.18
Cyclin D1-11 0.05 −0.23 0.03 0.20 −0.16 −0.25 −0.07 −0.08
STAT2-4 −0.09 0.03 −0.31 −0.04 0.08 0.06 −0.08 −0.04
TSC1-4 0.52 0.24 0.16 −0.09 0.48 0.21 0.24 0.43
Bad-22 0.30 0.10 0.23 0.06 0.16 0.16 0.46 0.39
FAPP-4 −0.17 −0.18 0.04 0.07 0.02 −0.23 0.22 0.05
FHO-6 0.31 0.22 0.27 0.19 0.06 0.04 0.15 0.19
F25 + lactacystin 0.26 0.36 0.33 0.15 0.04 0.27 0.23 0.36
F25 + ONO5046 0.29 −0.01 −0.17 −0.30 −0.03 0.37 0.05 0.10
F25 + CA-074 0.32 0.04 −0.04 −0.03 −0.07 0.17 0.11 0.08
F25 + PQQ 0.27 −0.05 −0.14 −0.13 −0.07 0.15 −0.01 −0.16
F25 + PD98059 −0.40 0.05 −0.20 −0.01 −0.21 0.08 0.04 −0.13
F25 + ALLN 0.06 0.10 0.08 −0.03 0.14 0.22 −0.10 0.15
F25 + ONO3403 0.43 0.38 0.30 0.20 0.19 0.23 0.31 0.55
F25 + Y27632 0.12 0.34 0.19 0.45 −0.11 −0.03 0.35 0.29
TABLE 6
PDGF-R PDGF-R Glucoc RhoA RhoA-D CaMKII: CaMKII PKCalph
PDGF-R 1.00
PDGF-R-Del 0.08 1.00
Glucocorticoid-R 0.03 0.37 1.00
RhoA 0.16 0.31 0.32 1.00
RhoA-DN 0.20 0.61 −0.02 0.29 1.00
CaMKIIa −0.15 −0.07 0.01 −0.12 0.04 1.00
CaMKIIa-Active 0.15 0.39 0.20 0.19 0.29 0.16 1.00
PKCalpha-KN 0.40 −0.05 0.05 0.45 0.19 −0.28 −0.19 1.00
PKCalpha-KN 0.11 0.40 0.09 0.24 0.45 0.03 0.02 0.21
PKCepsilon-KN 0.00 0.25 0.12 0.41 0.25 −0.06 −0.14 0.49
PKCepsilon-KN 0.20 0.10 0.12 0.03 0.02 −0.08 −0.21 0.07
TPA (PKC-) −0.18 0.20 0.11 −0.15 −0.03 −0.11 0.11 0.15
Akt-DN 0.49 −0.10 −0.08 0.00 −0.22 −0.02 −0.16 −0.01
ERK-DN −0.06 0.62 0.09 0.32 0.72 0.16 0.39 0.16
JNK-DN −0.12 0.53 0.14 0.10 0.28 0.12 −0.10 0.12
p38-DN −0.11 0.37 −0.13 0.05 0.56 0.15 0.17 0.12
cAMP-PK-CS 0.18 0.36 0.40 0.30 −0.15 −0.06 0.21 0.03
PKCalpt PKCeps PKCeps TPA (PK Akt-DN ERK-DN JNK-DI p38-DN cAMP
PDGF-R
PDGF-R-Del
Glucocorticoid-R
RhoA
RhoA-DN
CaMKIIa
CaMKIIa-Active
PKCalpha-KN
PKCalpha-KN 1.00
PKCepsilon-KN 0.13 1.00
PKCepsilon-KN 0.69 0.01 1.00
TPA (PKC-) 0.09 0.24 −0.20 1.00
Akt-DN 0.29 −0.17 0.44 0.00 1.00
ERK-DN 0.30 0.35 −0.14 0.11 −0.04 1.00
JNK-DN 0.31 0.10 0.19 0.30 0.16 0.37 1.00
p38-DN 0.45 0.09 0.17 0.16 0.15 0.63 0.54 1.00
cAMP-PK-CS 0.40 0.30 0.34 0.47 −0.01 0.06 0.13 −0.07 1.00
TABLE 7
PDGF-R PDGF-R-D Glucocor RhoA RhoA-DN CaMKIIa CaMKIIa-Ac PKCalpha PKCalpha PKCepsilL
14-3-3zWT −0.12 0.08 −0.02 −0.17 0.08 0.13 0.00 0.11 0.19 0.44
TK 0.02 −0.17 −0.06 −0.07 −0.28 0.11 −0.13 −0.27 −0.07 −0.21
caspase-1 0.07 0.18 0.07 0.05 0.16 0.17 0.41 −0.18 −0.30 −0.15
caspase-3 0.01 0.48 0.38 0.57 0.30 −0.14 0.32 0.20 0.06 0.34
caspase-2 0.13 0.37 0.06 0.09 0.44 −0.31 −0.12 0.44 0.21 0.24
cystatin alpha 0.24 0.42 0.19 0.54 0.35 0.05 0.43 0.05 0.23 −0.15
cystatin E 0.38 0.16 −0.01 0.25 0.18 −0.01 0.24 0.03 0.16 0.02
u-calpain 0.05 0.48 0.21 0.11 0.49 0.04 0.12 −0.03 0.11 −0.13
m-calpain 0.13 0.54 0.44 0.57 0.36 −0.15 0.15 0.13 0.38 0.31
calpain 0.12 −0.29 −0.02 −0.26 −0.01 −0.35 −0.37 0.38 0.11 −0.06
30K (N)
calpain 0.14 0.19 −0.08 −0.12 0.28 0.07 0.19 −0.12 −0.26 −0.04
30K (F)
calpastatin 0.02 −0.28 −0.10 −0.27 −0.27 0.19 −0.38 −0.02 0.25 −0.09
CP-antisense −0.10 0.30 −0.12 0.17 0.53 −0.01 0.15 0.17 0.35 0.31
BH −0.16 −0.04 −0.04 −0.12 0.18 0.35 0.05 −0.13 −0.03 −0.02
DAN 0.20 0.37 0.15 0.34 0.40 −0.18 0.05 0.28 0.03 0.30
Regucalcin 0.00 0.19 −0.01 0.04 0.25 0.18 0.05 −0.15 0.72 0.06
CathL-mut −0.33 −0.08 −0.21 −0.17 −0.01 0.32 −0.25 0.10 −0.01 0.46
STAT1 −0.01 0.44 0.78 0.34 −0.18 0.05 0.28 −0.15 0.01 0.12
CBP −0.10 0.47 0.21 0.18 0.61 0.30 0.50 −0.26 0.03 0.22
P/CAF 0.16 0.21 −0.05 0.11 0.36 −0.03 −0.03 0.02 0.13 0.03
HNF1 0.05 0.33 0.33 0.36 −0.13 0.07 0.29 −0.22 0.12 0.08
HNF3b −0.16 −0.03 −0.04 0.33 0.10 −0.07 −0.39 0.43 0.38 0.51
HNF4 −0.45 −0.06 −0.06 −0.15 −0.09 0.38 −0.06 −0.16 0.04 −0.09
coup −0.18 0.52 −0.01 0.29 0.36 0.18 0.56 −0.18 0.20 0.19
C/EBPa 0.03 0.19 0.06 0.31 0.24 −0.20 0.12 0.09 0.26 −0.06
C/EBPb 0.24 0.39 0.15 0.11 0.30 −0.42 0.20 0.17 0.09 0.22
per-1 0.21 0.02 0.02 0.04 0.15 0.01 −0.23 0.39 0.45 0.04
p33/ING1 0.00 0.30 −0.08 0.13 0.26 −0.01 0.35 −0.30 −0.03 −0.03
T.Tn 0.11 −0.23 0.06 −0.11 −0.26 0.15 0.06 −0.25 −0.02 −0.48
CD44/H-CAM 0.15 0.15 −0.10 −0.13 0.20 0.07 0.03 −0.15 0.03 −0.06
CD44/3E 0.38 0.16 −0.01 −0.38 0.34 −0.19 0.01 −0.27 −0.30 −0.19
CD44/3s 0.05 0.04 −0.05 −0.15 0.35 −0.08 −0.26 −0.07 −0.31 0.07
Jagged-1 −0.06 −0.01 0.04 0.13 0.09 0.14 0.31 −0.05 −0.17 −0.08
p94-WT −0.41 0.47 0.02 0.10 0.25 −0.20 0.18 −0.13 −0.02 0.18
p94-mut −0.28 0.26 0.07 −0.02 −0.24 −0.23 −0.15 −0.05 −0.05 0.07
E2F-High 0.03 0.12 0.04 −0.07 0.03 −0.10 −0.12 −0.17 −0.14 0.19
14-3-3zWT −0.12 0.08 −0.02 −0.17 0.08 0.13 0.00 0.11 0.19 0.44
PKCepsil TPA (PKC-) Akt-DN ERK-DN JNK-DN p38-DN cAMP-PK- 14-3-3W TK caspase-1
14-3-3zWT 0.07 0.33 0.13 0.21 0.09 0.17 0.13 1.00
TK −0.06 −0.26 0.08 −0.26 −0.23 −0.22 −0.27 −0.02 1.00
caspase-1 −0.46 0.10 −0.17 0.33 0.01 0.12 −0.09 −0.30 −0.02 1.00
caspase-3 −0.31 0.21 −0.12 0.60 0.15 0.21 0.19 0.01 −0.02 0.49
caspase-2 −0.03 0.19 −0.03 0.41 0.27 0.30 −0.01 0.20 −0.25 −0.09
cystatin alpha −0.05 0.05 0.23 0.46 0.15 0.26 0.29 −0.14 −0.12 0.69
cystatin E 0.16 0.01 0.57 0.41 0.13 0.27 0.02 0.23 0.19 0.20
u-calpain −0.10 −0.03 0.23 0.35 0.48 0.41 −0.16 0.04 −0.16 0.18
m-calpain 0.00 0.16 −0.15 0.23 0.24 0.15 0.43 0.10 −0.25 0.06
calpain 30K (N) 0.24 −0.02 0.13 −0.50 −0.19 −0.23 −0.10 0.05 −0.08 −0.48
calpain 30K (F) −0.44 −0.01 0.24 0.20 0.10 0.03 −0.11 0.21 0.14 0.15
calpastatin 0.44 −0.29 0.00 −0.49 −0.25 −0.19 −0.11 0.08 0.32 −0.34
CP-antisense 0.06 0.08 0.11 0.68 0.06 0.60 0.03 0.17 −0.16 0.16
BH 0.05 0.05 0.26 −0.01 0.15 0.25 −0.26 0.23 0.17 −0.23
DAN −0.21 0.19 −0.01 0.47 0.22 0.23 0.16 0.16 −0.06 0.22
Regucalcin 0.65 0.11 0.35 0.02 0.24 0.34 0.14 0.25 −0.06 −0.36
CathL-mut −0.10 0.11 −0.21 0.00 0.07 0.11 −0.02 0.43 0.08 −0.26
STAT1 0.04 0.23 0.12 0.11 0.29 −0.05 0.52 0.09 0.07 0.07
CBP −0.14 −0.14 −0.25 0.56 −0.03 0.17 −0.01 0.12 −0.05 0.34
P/CAF −0.21 0.02 −0.14 0.16 0.00 −0.14 −0.13 0.06 0.25 −0.01
HNF1 −0.03 0.06 0.25 0.17 0.07 −0.06 0.32 0.15 0.17 0.09
HNF3b 0.26 0.02 0.21 0.07 0.16 0.25 −0.08 0.38 0.19 −0.31
HNF4 −0.01 0.09 0.15 0.11 0.26 0.13 −0.05 0.24 0.02 −0.21
coup −0.17 0.10 0.05 0.64 0.12 0.42 0.24 0.22 −0.04 0.19
C/EBPa −0.07 0.02 −0.08 0.27 −0.02 0.09 0.02 −0.05 0.37 0.22
C/EBPb −0.09 0.05 −0.01 0.47 0.04 0.05 0.13 0.12 0.01 −0.04
per-1 0.30 0.24 0.39 0.14 0.47 0.45 −0.04 0.27 −0.18 −0.13
p33/ING1 −0.20 −0.08 −0.30 0.13 −0.10 −0.08 0.11 −0.12 0.16 0.03
T.Tn 0.02 −0.31 0.05 −0.29 −0.20 −0.22 −0.06 −0.18 0.40 0.07
CD44/H-CAM 0.21 −0.09 0.15 0.07 0.07 0.07 0.27 0.07 −0.12 −0.22
CD44/3E 0.00 −0.19 −0.09 −0.07 −0.19 −0.21 −0.19 −0.07 0.01 −0.08
CD44/3s −0.31 −0.18 −0.12 −0.01 −0.24 −0.18 −0.21 0.05 0.11 −0.15
Jagged-1 −0.18 −0.05 −0.29 0.00 −0.11 0.07 −0.07 −0.09 −0.06 0.26
p94-WT −0.29 0.23 −0.25 0.19 0.27 0.17 −0.07 0.32 −0.07 −0.06
p94-mut −0.09 0.23 0.13 −0.11 0.44 0.02 0.12 0.15 −0.17 −0.29
E2F-High −0.13 0.09 0.32 −0.03 0.11 0.03 −0.01 0.41 −0.08 −0.16
14-3-3zWT 0.07 0.33 0.13 0.21 0.09 0.17 0.13 1.00
indicates data missing or illegible when filed
TABLE 8
PDGF-R PDGF-R-D Glucocor RhoA RhoA-DN CaMKIIa CaMKIIa-Ac PKCalpha PKCalpha PKCepsil
E2F-Low −0.07 −0.19 0.05 −0.10 −0.25 0.10 −0.16 −0.33 −0.22 0.17
FBRCA1-13 0.00 −0.29 −0.16 0.09 0.03 0.07 −0.08 0.24 −0.11 0.02
FMDM2hwt-6 −0.04 −0.31 −0.12 −0.09 −0.01 0.15 −0.08 0.10 −0.08 −0.19
p27-3 −0.49 0.23 0.08 0.27 0.19 0.24 0.18 −0.08 −0.21 0.30
CAPN10-10 −0.06 0.47 0.25 0.13 −0.13 −0.09 0.19 −0.32 0.07 −0.05
c-myc-1 −0.21 0.37 0.18 −0.03 −0.08 −0.04 0.17 −0.17 0.04 −0.01
MSSP-10 −0.23 −0.41 −0.17 −0.18 0.02 0.28 0.14 −0.15 −0.26 0.01
MM1 0.28 0.18 −0.15 0.26 0.29 −0.26 0.27 0.15 −0.05 0.14
AMY1 −0.18 0.28 0.25 0.15 −0.05 0.00 0.11 −0.14 0.09 0.25
Max 0.00 0.21 0.12 0.24 0.04 −0.03 0.10 0.01 −0.07 0.21
MDM2-hmut −0.16 0.48 0.23 0.34 0.33 −0.17 0.31 0.00 0.11 0.23
MDM2-mWT 0.08 0.02 0.05 −0.01 −0.19 −0.19 0.12 −0.10 0.06 0.07
TERT-WT 0.02 −0.09 −0.06 −0.05 −0.32 −0.22 −0.34 0.19 −0.11 0.15
TERT-DN 0.45 0.30 0.11 0.21 0.14 −0.30 0.18 0.08 −0.06 0.00
PTEN-WT 0.05 0.28 0.39 0.14 0.05 −0.04 0.15 −0.07 −0.14 0.16
PTEN-A3 −0.32 0.08 0.01 0.14 −0.01 0.10 0.03 −0.11 0.08 0.17
PTEN-G129R −0.01 0.10 0.37 0.24 −0.27 0.00 0.07 −0.16 −0.05 −0.01
Bcl-2 −0.10 0.19 −0.03 0.03 0.19 0.02 0.00 0.05 0.01 0.20
per2 0.18 0.47 0.27 0.13 0.15 0.08 0.19 −0.14 0.27 −0.02
per3 0.15 0.31 0.42 0.31 0.04 0.23 0.21 −0.06 0.37 −0.09
Cyclin D1-11 0.27 −0.18 0.05 0.11 −0.09 0.21 0.04 −0.23 −0.24 −0.18
STAT2-4 −0.10 0.14 0.29 −0.06 −0.19 0.31 0.13 −0.14 0.09 0.10
TSC1-4 −0.36 0.17 0.03 0.27 0.33 0.15 −0.04 0.32 0.25 0.54
Bad-22 0.13 0.24 0.04 0.37 0.35 0.11 0.00 0.09 0.25 0.14
FAPP-4 −0.06 −0.26 −0.15 −0.34 −0.24 0.22 −0.25 −0.20 −0.28 0.06
FHO-6 −0.20 0.48 0.26 0.25 0.34 0.34 0.41 −0.01 0.23 0.24
F25 + lactacystin −0.09 0.44 0.09 0.31 0.40 0.04 0.33 0.13 0.23 0.17
F25 + ONO5046 −0.46 0.10 −0.09 0.05 0.16 0.17 0.09 0.02 −0.07 0.09
F25 + CA-074 −0.30 0.06 −0.17 0.04 0.14 0.30 0.12 −0.18 −0.01 0.09
F25 + PQQ −0.39 −0.09 −0.18 −0.01 0.05 0.34 0.22 −0.15 −0.16 −0.02
F25 + PD98059 −0.06 0.29 0.09 0.08 −0.32 −0.23 0.05 −0.29 0.05 −0.09
F25 + ALLN −0.03 0.33 −0.11 0.16 0.15 −0.25 −0.02 0.25 0.41 0.11
F25 + ONO3403 −0.45 0.50 0.12 0.25 0.52 0.10 0.19 0.02 0.33 0.41
F25 + Y27632 −0.08 0.43 0.20 0.16 0.23 0.24 0.24 −0.17 0.41 0.07
PKCepsil TPA (PKC-) Akt-DN ERK-DN JNK-DN p38-DN cAMP-PK- 14-3-3zw TK caspase-1
E2F-Low −0.01 −0.05 0.30 −0.18 −0.38 −0.32 −0.02 0.34 0.18 −0.04
FBRCA1-13 0.02 −0.17 −0.09 −0.04 −0.17 −0.01 −0.23 −0.05 −0.25 −0.15
FMDM2hwt-6 0.16 −0.16 −0.12 −0.31 0.03 0.08 −0.35 −0.01 −0.19 −0.08
p27-3 −0.20 −0.06 −0.15 0.34 0.09 0.13 −0.05 0.20 −0.05 0.04
CAPN10-10 −0.08 0.10 0.23 0.30 0.25 0.01 0.31 0.03 0.31 0.23
c-myc-1 0.04 0.26 0.22 0.28 0.41 0.32 0.23 0.22 −0.08 0.15
MSSP-10 −0.07 −0.16 −0.10 −0.17 −0.31 0.02 −0.34 0.18 −0.13 −0.01
MM1 −0.08 0.33 0.20 0.32 0.13 0.10 0.20 0.16 −0.31 0.11
AMY1 0.00 0.19 −0.06 0.18 −0.20 −0.09 0.36 0.21 0.21 0.03
Max −0.11 0.03 −0.19 0.26 −0.21 −0.13 0.25 0.02 0.24 0.18
MDM2-hmut −0.27 0.36 0.17 0.53 0.08 0.24 0.30 0.20 −0.01 0.18
MDM2-mWT 0.03 0.26 0.52 0.07 −0.16 0.07 0.28 0.31 −0.06 0.02
TERT-WT 0.02 0.11 0.00 −0.15 −0.13 −0.03 0.23 0.00 −0.10 −0.15
TERT-DN −0.19 0.02 0.11 0.29 0.03 −0.15 0.24 −0.09 0.12 0.21
PTEN-WT −0.15 0.08 −0.09 0.17 0.01 −0.16 0.25 −0.06 −0.11 0.32
PTEN-A3 −0.06 0.12 −0.24 0.17 0.16 0.02 0.13 −0.11 −0.06 0.26
PTEN-G129R −0.08 −0.02 0.26 0.00 −0.08 −0.34 0.18 0.01 0.21 0.15
Bcl-2 −0.20 0.20 −0.16 0.27 0.02 0.15 0.18 0.01 −0.02 0.02
per2 0.13 0.24 0.03 0.19 0.25 −0.02 0.40 −0.01 0.16 0.05
per3 0.22 0.25 −0.02 −0.03 0.21 −0.08 0.38 0.04 0.17 −0.05
Cyclin D1-11 0.01 −0.23 −0.15 −0.36 −0.30 −0.39 −0.07 −0.11 0.16 −0.10
STAT2-4 0.28 0.12 −0.37 −0.08 0.15 0.01 0.41 0.11 −0.12 −0.12
TSC1-4 −0.01 0.36 −0.10 0.36 0.32 0.37 0.29 0.32 −0.25 −0.15
Bad-22 −0.03 −0.26 −0.02 0.13 0.17 0.14 −0.04 0.07 0.19 0.00
FAPP-4 0.03 −0.03 0.04 −0.28 −0.09 −0.24 0.01 0.25 0.10 −0.21
FHO-6 0.05 0.28 −0.23 0.31 0.43 0.23 0.26 0.26 −0.20 0.05
F25 + lactacystin −0.15 0.31 −0.22 0.29 0.21 0.20 0.21 0.37 −0.21 0.05
F25 + ONO5046 −0.16 0.15 −0.28 0.15 0.11 0.29 0.03 0.17 −0.07 −0.13
F25 + CA-074 −0.07 0.12 −0.28 0.03 −0.05 0.11 0.12 0.19 −0.08 −0.04
F25 + PQQ −0.06 0.00 −0.30 −0.07 −0.08 0.08 −0.02 0.03 −0.12 0.00
F25 + PD98059 −0.01 −0.03 0.12 0.04 0.14 −0.05 0.22 0.03 0.22 0.05
F25 + ALLN 0.16 0.26 0.00 0.37 0.52 0.41 0.17 0.07 −0.17 0.09
F25 + ONO3403 −0.13 0.30 −0.16 0.53 0.30 0.51 0.22 0.38 −0.24 0.03
F25 + Y27632 0.11 0.14 0.28 0.37 0.21 0.23 0.18 0.29 0.10 0.06
indicates data missing or illegible when filed
TABLE 9
caspase-3 caspase-2 cystatin al cystatin E u-calpain m-calpain calpain 30K calpain 30K
caspase-3 1.00
caspase-2 0.41 1.00
cystatin alpha 0.56 0.09 1.00
cystatin E 0.32 0.33 0.54 1.00
u-calpain 0.25 0.31 0.37 0.27 1.00
m-calpain 0.45 0.23 0.52 0.08 0.41 1.00
calpain 30K (N) −0.43 0.03 −0.40 −0.37 −0.16 −0.25 1.00
calpain 30K (F) 0.12 0.18 0.21 0.43 0.55 0.14 0.13 1.00
calpastatin −0.53 −0.17 −0.35 −0.21 −0.18 −0.23 0.14 −0.20
CP-antisense 0.38 0.25 0.28 0.31 0.09 −0.02 −0.28 0.01
BH −0.18 0.08 −0.24 0.30 0.31 −0.12 −0.26 0.23
DAN 0.68 0.69 0.54 0.45 0.33 0.35 −0.37 0.32
Regucalcin −0.16 0.02 −0.04 0.21 0.37 0.24 0.17 0.14
CathL-mut −0.20 −0.04 −0.39 0.01 −0.13 0.01 −0.09 0.00
STAT1 0.40 −0.01 0.22 0.23 0.20 0.37 −0.10 0.11
CBP 0.41 0.10 0.32 0.32 0.16 0.17 −0.42 0.24
P/CAF 0.21 0.27 0.02 0.04 0.28 0.32 0.32 0.34
HNF1 0.44 −0.10 0.34 0.20 0.24 0.40 −0.42 0.13
HNF3b 0.06 0.13 −0.11 0.17 −0.01 0.02 0.27 −0.01
HNF4 −0.15 −0.05 −0.09 −0.08 0.04 −0.15 −0.37 0.01
coup 0.42 0.06 0.35 0.35 0.31 0.34 −0.66 0.20
C/EBPa 0.50 0.27 0.51 0.40 0.21 0.04 −0.26 0.19
C/EBPb 0.40 0.22 −0.07 0.02 0.17 0.20 0.02 0.14
per-1 −0.06 0.35 0.13 0.25 0.27 0.06 0.24 0.14
p33/ING1 0.12 −0.15 −0.03 −0.21 0.17 0.23 0.10 0.22
T.Tn −0.24 −0.39 0.09 −0.07 −0.10 −0.16 −0.07 0.00
CD44/H-CAM −0.21 −0.06 −0.20 −0.12 0.14 0.01 0.34 0.24
CD44/3E −0.16 0.21 −0.29 0.04 0.09 −0.17 0.31 0.32
CD44/3s −0.03 0.10 −0.25 −0.06 0.17 −0.02 0.43 0.45
Jagged-1 −0.03 −0.15 0.25 0.10 −0.01 −0.11 −0.37 0.04
p94-WT 0.29 0.24 −0.17 −0.09 0.36 0.41 −0.11 0.30
p94-mut −0.06 0.08 −0.21 −0.06 0.22 0.25 0.02 0.13
E2F-High −0.02 0.09 0.03 0.26 0.46 0.30 0.15 0.50
calpastatin CP-antisens BH DAN Regucalc CathL-mut STAT1 CBP P/CAF HNF1
caspase-3
caspase-2
cystatin alpha
cystatin E
u-calpain
m-calpain
calpain 30K (N)
calpain 30K (F)
calpastatin 1.00
CP-antisense −0.19 1.00
BH 0.13 0.04 1.00
DAN −0.36 0.35 −0.03 1.00
Regucalcin 0.16 0.13 0.47 −0.05 1.00
CathL-mut 0.31 0.11 0.27 −0.13 0.20 1.00
STAT1 −0.20 −0.17 0.05 0.13 0.08 −0.14 1.00
CBP −0.35 0.42 0.19 0.26 0.14 0.13 0.17 1.00
P/CAF −0.10 −0.11 −0.07 0.33 0.05 −0.15 −0.04 0.05 1.00
HNF1 −0.21 0.02 0.03 0.28 0.20 −0.14 0.44 0.16 0.15 1.00
HNF3b 0.22 0.29 0.17 0.17 0.30 0.40 −0.08 −0.11 −0.02 0.16
HNF4 −0.05 0.09 0.33 −0.01 0.10 0.17 −0.11 0.04 −0.16 0.22
coup −0.24 0.54 0.21 0.26 0.22 0.16 0.15 0.45 0.11 0.53
C/EBPa −0.14 0.31 −0.10 0.67 −0.08 −0.30 0.02 0.08 0.39 0.20
C/EBPb −0.40 0.30 −0.28 0.36 −0.15 −0.17 0.08 0.11 0.26 0.34
per-1 −0.07 0.09 0.05 0.17 0.33 0.01 −0.03 −0.24 −0.02 −0.06
p33/ING1 −0.31 −0.01 −0.20 0.10 0.09 −0.08 0.08 0.32 0.50 0.25
T.Tn 0.27 −0.19 −0.10 −0.18 −0.14 −0.26 −0.10 −0.16 −0.06 0.18
CD44/H-CAM −0.07 0.16 −0.06 0.09 0.12 0.05 0.08 0.18 −0.05 −0.15
CD44/3E −0.05 −0.08 0.13 0.14 0.01 −0.35 −0.11 0.38 0.19 −0.17
CD44/3s −0.08 0.06 0.11 0.19 0.04 0.05 −0.14 0.32 0.32 −0.10
Jagged-1 0.09 0.06 0.18 −0.06 −0.08 0.29 −0.01 0.41 −0.39 −0.13
p94-WT −0.12 −0.06 0.15 0.08 0.10 0.16 0.15 0.16 0.25 0.30
p94-mut −0.03 −0.33 0.09 −0.17 0.07 0.16 0.30 −0.34 −0.02 0.11
E2F-High −0.07 −0.23 0.35 0.12 0.37 0.12 0.20 −0.03 0.15 0.33
indicates data missing or illegible when filed
TABLE 10
caspase-3 caspase-2 cystatin al cystatin E u-calpain m-calpain calpain 30K calpain 30K calpastatin
E2F-Low −0.04 −0.19 −0.07 0.20 0.06 −0.04 −0.06 0.27 0.19
FBRCA1-13 −0.04 0.02 −0.30 −0.14 0.01 −0.15 0.16 0.03 −0.01
FMDM2hwt-6 −0.39 −0.13 −0.19 −0.12 0.04 −0.24 0.07 −0.08 0.38
p27-3 0.29 0.05 −0.13 0.07 0.13 0.09 −0.51 0.18 −0.06
CAPN10-10 0.44 −0.01 0.37 0.32 0.21 0.18 −0.30 0.24 −0.28
c-myc-1 0.26 0.13 0.25 0.36 0.38 0.27 −0.55 0.15 −0.29
MSSP-10 −0.26 −0.23 −0.21 0.01 0.03 −0.22 −0.02 0.10 0.35
MM1 0.32 0.17 0.30 0.41 0.33 0.27 −0.25 0.26 −0.57
AMY1 0.35 −0.08 0.16 0.16 −0.05 0.32 −0.09 0.03 −0.19
Max 0.39 −0.10 0.34 0.18 −0.05 0.23 −0.14 0.15 −0.25
MDM2-hmut 0.61 0.26 0.40 0.31 0.36 0.41 −0.22 0.37 −0.48
MDM2-mWT 0.16 0.08 0.28 0.55 0.01 0.11 −0.15 0.07 −0.17
TERT-WT −0.06 −0.08 −0.13 −0.05 −0.13 0.13 0.28 −0.21 0.00
TERT-DN 0.50 0.30 0.39 0.30 0.29 0.32 −0.09 0.38 −0.49
PTEN-WT 0.44 −0.06 0.22 −0.22 0.27 0.38 −0.22 −0.03 −0.21
PTEN-A3 0.32 −0.06 0.26 −0.08 −0.22 0.24 −0.07 −0.12 −0.42
PTEN-G129R 0.45 −0.08 0.29 0.11 0.16 0.24 −0.09 0.14 −0.17
Bcl-2 0.21 0.14 0.05 0.18 −0.01 0.24 −0.11 −0.01 −0.32
per2 0.23 0.15 0.21 0.18 0.24 0.42 −0.07 0.14 −0.18
per3 0.13 −0.02 0.20 0.11 0.18 0.41 −0.07 0.02 0.03
Cyclin D1-11 −0.25 −0.35 0.01 −0.24 −0.13 −0.07 0.05 0.00 0.25
STAT2-4 −0.18 −0.17 −0.08 −0.08 −0.20 0.15 −0.52 −0.36 0.30
TSC1-4 0.25 0.30 −0.19 0.07 0.23 0.39 0.31 0.16 −0.27
Bad-22 0.15 0.07 0.25 0.01 0.50 0.36 0.11 0.37 0.04
FAPP-4 −0.54 −0.21 −0.28 0.03 −0.12 −0.18 0.05 0.03 0.39
FHO-6 0.13 0.01 −0.01 −0.21 0.26 0.39 −0.17 0.03 −0.01
F25 + lactacystin 0.34 0.38 0.37 0.05 0.25 0.45 −0.23 0.10 −0.20
F25 + ONO5046 0.01 0.17 −0.07 −0.06 −0.02 −0.14 −0.17 −0.11 0.18
F25 + CA-074 −0.09 −0.17 −0.08 −0.06 −0.02 0.02 −0.30 −0.05 0.25
F25 + PQQ −0.23 −0.36 −0.21 −0.21 −0.14 −0.08 −0.24 −0.14 0.30
F25 + PD98059 0.16 0.02 0.37 0.19 −0.04 0.06 −0.39 −0.07 −0.10
F25 + ALLN 0.32 0.41 0.26 0.08 0.16 0.22 −0.17 −0.09 −0.31
F25 + ONO3403 0.47 0.28 0.19 0.05 0.26 0.52 −0.41 0.17 −0.40
F25 + Y27632 0.40 0.17 0.30 0.39 0.28 0.25 −0.37 0.36 −0.08
CP-antisens BH DAN Regucalc CathL-mut STAT1 CBP P/CAF HNF1
E2F-Low 0.01 0.24 0.02 0.27 0.17 0.09 0.14 −0.09 0.41
FBRCA1-13 0.09 −0.06 0.01 0.01 −0.14 −0.31 −0.03 −0.05 −0.09
FMDM2hwt-6 −0.15 0.19 −0.31 0.21 0.15 −0.26 −0.12 −0.33 −0.40
p27-3 0.33 0.23 0.26 −0.03 0.25 0.11 0.48 −0.09 0.33
CAPN10-10 0.07 −0.14 0.25 −0.10 −0.16 0.52 0.11 0.18 0.56
c-myc-1 0.10 0.09 0.20 0.03 0.15 0.35 0.10 −0.18 0.40
MSSP-10 0.01 0.35 −0.21 0.23 0.29 −0.23 0.13 −0.24 −0.21
MM1 0.22 0.01 0.47 0.08 −0.14 −0.01 0.13 0.19 0.32
AMY1 0.25 −0.07 0.17 0.06 0.11 0.29 0.22 0.26 0.45
Max 0.15 −0.24 0.26 −0.10 0.02 0.18 0.22 0.25 0.35
MDM2-hmut 0.43 0.01 0.55 0.17 −0.05 0.33 0.32 0.22 0.50
MDM2-mWT 0.27 0.05 0.16 0.16 0.03 0.22 −0.03 −0.14 0.44
TERT-WT 0.00 −0.18 −0.22 −0.06 0.11 0.00 −0.37 −0.14 0.05
TERT-DN −0.02 −0.29 0.58 −0.19 −0.41 0.18 0.04 0.50 0.45
PTEN-WT 0.02 −0.21 0.23 −0.08 −0.34 0.26 0.06 0.22 0.42
PTEN-A3 −0.07 −0.37 0.15 −0.17 −0.12 0.07 0.13 0.22 0.02
PTEN-G129R −0.05 −0.22 0.37 −0.01 −0.34 0.40 0.01 0.28 0.78
Bcl-2 0.20 −0.04 0.23 0.01 0.26 0.04 0.11 0.25 0.09
per2 −0.07 0.02 0.22 0.12 −0.09 0.34 0.16 0.44 0.21
per3 −0.23 0.16 0.03 0.24 −0.06 0.40 0.13 0.25 0.18
Cyclin D1-11 −0.38 0.11 −0.20 0.13 −0.16 0.05 0.00 0.07 0.04
STAT2-4 −0.18 0.20 −0.26 0.12 0.43 0.26 0.10 −0.35 0.04
TSC1-4 0.26 0.13 0.39 0.23 0.31 0.09 0.18 0.22 0.02
Bad-22 −0.02 0.07 0.30 0.27 0.16 0.05 0.20 0.30 0.22
FAPP-4 −0.20 0.26 −0.26 0.04 0.40 −0.09 −0.17 −0.04 −0.11
FHO-6 −0.02 0.03 0.00 0.29 0.12 0.27 0.22 0.14 0.18
F25 + lactacystin 0.10 0.14 0.41 0.13 0.08 0.10 0.30 0.28 0.28
F25 + ONO5046 0.09 0.31 0.17 0.02 0.34 0.02 0.09 −0.17 −0.09
F25 + CA-074 0.10 0.34 −0.11 0.20 0.42 −0.08 0.22 −0.19 −0.08
F25 + PQQ 0.05 0.24 −0.31 0.13 0.42 −0.17 0.18 −0.38 −0.12
F25 + PD98059 −0.10 −0.03 0.02 −0.17 0.00 0.34 −0.07 −0.14 0.31
F25 + ALLN 0.18 −0.21 0.29 −0.08 −0.07 −0.04 −0.15 0.06 0.04
F25 + ONO3403 0.41 0.15 0.39 0.22 0.10 0.12 0.45 0.20 0.24
F25 + Y27632 0.29 0.23 0.30 0.32 −0.02 0.30 0.40 0.16 0.54
indicates data missing or illegible when filed
TABLE 11
HNF3b HNF4 coup C/EBPa C/EBPb per-1 p33/ING1
HNF3b 1.00
HNF4 0.06 1.00
coup 0.01 0.17 1.00
C/EBPa 0.19 −0.11 0.20 1.00
C/EBPb 0.10 −0.02 0.34 0.40 1.00
per-1 0.47 0.11 −0.25 0.01 −0.06 1.00
p33/ING1 −0.29 −0.11 0.32 0.25 0.31 −0.31 1.00
T.Tn 0.02 0.17 −0.12 0.16 −0.04 −0.01 −0.10
CD44/H-CAM −0.23 0.06 0.10 −0.06 0.09 −0.11 0.45
CD44/3E −0.24 −0.11 −0.27 0.02 0.02 −0.10 0.16
CD44/3s −0.01 −0.05 −0.10 0.08 0.11 −0.16 0.31
Jagged-1 −0.11 −0.02 0.09 0.04 −0.28 −0.12 −0.01
p94-WT 0.04 0.02 0.39 −0.01 0.22 −0.16 0.23
p94-mut 0.04 0.06 0.07 −0.26 0.06 0.02 −0.06
E2F-High 0.25 −0.02 0.12 −0.15 0.10 0.14 −0.06
T.Tn CD44/H-CAM CD44/3E CD44/3s Jagged-1 p94-WT p94-mut E2F-High
HNF3b
HNF4
coup
C/EBPa
C/EBPb
per-1
p33/ING1
T.Tn 1.00
CD44/H-CAM −0.11 1.00
CD44/3E 0.10 0.18 1.00
CD44/3s 0.01 0.19 0.67 1.00
Jagged-1 0.01 −0.01 0.17 0.08 1.00
p94-WT −0.27 −0.11 0.04 0.14 0.04 1.00
p94-mut −0.24 0.00 −0.22 −0.20 −0.20 0.62 1.00
E2F-High −0.10 −0.10 0.15 0.28 −0.13 0.39 0.36 1.00
TABLE 12
HNF3b HNF4 coup C/EBPa C/EBPb per-1 p33/ING1 T.Tn
E2F-Low 0.24 0.10 0.11 −0.09 −0.04 −0.14 −0.12 0.09
FBRCA1-13 0.04 0.10 −0.21 0.02 −0.09 0.06 0.03 −0.07
FMDM2hwt-6 0.11 0.03 −0.43 −0.17 −0.47 0.27 −0.27 −0.01
p27-3 0.13 0.29 0.52 −0.03 0.05 −0.27 0.14 −0.10
CAPN10-10 −0.06 0.02 0.47 0.32 0.46 −0.18 0.27 0.09
c-myc-1 −0.01 0.16 0.46 −0.08 0.24 0.07 −0.03 −0.07
MSSP-10 0.02 −0.12 −0.02 −0.23 −0.39 −0.18 −0.12 −0.10
MM1 −0.13 −0.01 0.42 0.23 0.45 −0.06 0.28 −0.23
AMY1 0.07 0.06 0.47 0.28 0.22 −0.28 0.37 0.01
Max 0.07 −0.08 0.30 0.34 0.24 −0.24 0.34 0.08
MDM2-hmut 0.18 0.04 0.61 0.45 0.56 0.08 0.26 −0.12
MDM2-mWT 0.26 −0.06 0.34 0.11 0.23 0.15 −0.22 0.02
TERT-WT 0.11 −0.07 −0.06 −0.19 −0.01 −0.04 −0.15 0.01
TERT-DN −0.17 −0.16 0.22 0.55 0.62 −0.04 0.36 0.01
PTEN-WT −0.21 −0.10 0.23 0.08 0.29 −0.29 0.18 0.14
PTEN-A3 −0.09 −0.10 −0.02 0.04 −0.06 −0.05 0.23 −0.10
PTEN-G129R 0.04 0.01 0.21 0.25 0.27 −0.11 0.22 0.19
Bcl-2 0.09 −0.02 0.28 0.14 0.24 −0.02 0.22 −0.05
per2 −0.27 0.02 0.32 0.16 0.14 −0.07 0.36 0.03
per3 −0.23 0.12 0.15 0.08 −0.18 −0.02 0.18 0.18
Cyclin D1-11 −0.13 −0.02 −0.34 −0.02 −0.30 −0.13 0.15 0.16
STAT2-4 −0.14 0.23 0.10 −0.30 −0.29 −0.17 −0.10 −0.05
TSC1-4 0.20 0.03 0.29 −0.05 0.04 0.14 0.17 −0.30
Bad-22 0.22 −0.03 0.19 0.24 0.16 0.11 0.33 0.10
FAPP-4 0.07 0.05 −0.02 −0.28 −0.18 −0.12 −0.16 0.06
FHO-6 0.05 0.03 0.32 −0.11 −0.01 0.14 0.17 −0.04
F25 + lactacystin 0.06 0.10 0.39 0.19 0.05 0.02 0.15 −0.12
F25 + ONO5046 0.18 0.00 0.21 0.12 −0.09 −0.05 0.00 −0.08
F25 + CA-074 −0.06 0.10 0.30 −0.02 −0.26 −0.30 0.04 −0.08
F25 + PQQ −0.02 0.11 0.21 −0.28 −0.35 −0.24 −0.01 0.05
F25 + PD98059 −0.07 −0.01 0.26 0.12 0.16 −0.16 −0.04 0.04
F25 + ALLN 0.11 0.13 0.19 0.22 0.30 0.20 −0.06 −0.16
F25 + ONO3403 0.17 0.12 0.47 0.17 0.22 0.04 0.16 −0.30
F25 + Y27632 0.20 0.30 0.45 0.25 0.16 0.16 0.10 −0.06
CD44/H-CAM CD44/3E CD44/3s Jagged-1 p94-WT p94-mut E2F-High
E2F-Low −0.05 0.14 0.31 −0.03 0.06 −0.09 0.57
FBRCA1-13 0.03 0.22 0.22 0.12 0.02 −0.13 −0.12
FMDM2hwt-6 −0.11 0.17 0.01 0.47 −0.05 −0.06 −0.13
p27-3 0.16 0.05 0.19 0.33 0.39 −0.04 0.01
CAPN10-10 0.12 −0.23 −0.19 −0.24 0.26 0.32 0.13
c-myc-1 0.21 −0.25 −0.29 0.03 0.31 0.31 0.23
MSSP-10 −0.03 0.09 0.13 0.38 0.09 −0.08 0.17
MM1 0.31 −0.03 0.05 −0.12 0.16 0.00 0.16
AMY1 0.06 −0.23 −0.03 −0.20 0.10 −0.01 0.00
Max 0.11 0.01 0.18 −0.09 −0.07 −0.23 −0.03
MDM2-hmut 0.12 −0.12 0.12 −0.11 0.29 0.07 0.25
MDM2-mWT −0.18 −0.14 −0.16 −0.15 −0.09 0.05 0.35
TERT-WT −0.15 −0.17 0.08 −0.34 −0.09 0.17 0.09
TERT-DN 0.09 0.13 0.12 −0.35 0.01 −0.01 0.14
PTEN-WT −0.06 −0.04 0.00 −0.33 0.12 0.03 0.06
PTEN-A3 −0.08 −0.30 −0.32 −0.33 0.04 0.14 −0.16
PTEN-G129R −0.17 −0.11 0.03 −0.35 0.05 −0.01 0.10
Bcl-2 0.14 −0.05 0.08 −0.15 −0.08 0.03 −0.01
per2 0.28 −0.03 −0.13 −0.24 0.11 0.16 −0.03
per3 0.14 −0.01 −0.02 0.02 0.15 0.10 −0.08
Cyclin D1-11 0.00 0.37 0.20 0.10 −0.15 −0.14 0.06
STAT2-4 0.01 −0.17 −0.39 0.41 0.01 0.08 −0.12
TSC1-4 0.28 −0.19 0.13 −0.09 0.25 0.02 0.10
Bad-22 0.20 −0.04 0.33 0.03 0.22 −0.07 0.22
FAPP-4 0.05 −0.07 −0.05 0.01 −0.13 0.04 0.25
FHO-6 0.01 −0.16 −0.23 0.01 0.43 0.24 0.04
F25 + lactacystin 0.01 0.09 0.04 0.16 0.44 0.07 0.09
F25 + ONO5046 −0.01 −0.04 0.06 0.42 0.20 −0.01 −0.01
F25 + CA-074 0.21 −0.03 0.20 0.49 0.29 −0.03 0.00
F25 + PQQ 0.09 −0.13 0.01 0.53 0.20 −0.06 −0.18
F25 + PD98059 −0.03 −0.26 −0.36 −0.01 0.21 0.43 0.08
F25 + ALLN 0.00 −0.37 −0.50 −0.15 0.32 0.33 −0.08
F25 + ONO3403 0.06 0.02 0.15 −0.02 0.48 0.13 0.22
F25 + Y27632 0.01 0.00 −0.09 −0.06 0.25 0.03 0.20
TABLE 13
E2F-Low FBRCA1-13 FMDM2hwt-6 p27-3 CAPN10-10 c-myc-1 MSSP-10 MM1
E2F-Low 1.00
FBRCA1-13 0.08 1.00
FMDM2hwt-6 −0.02 0.48 1.00
p27-3 0.26 0.22 −0.04 1.00
CAPN10-10 0.08 −0.57 −0.70 0.13 1.00
c-myc-1 0.05 −0.37 −0.38 0.36 0.60 1.00
MSSP-10 0.38 0.40 0.59 0.29 −0.47 −0.19 1.00
MM1 0.04 0.00 −0.38 0.23 0.32 0.42 −0.08 1.00
AMY1 0.21 −0.16 −0.57 0.21 0.49 0.16 −0.32 0.29
Max 0.14 0.03 −0.47 0.16 0.33 0.13 −0.23 0.25
MDM2-hmut 0.19 −0.19 −0.51 0.30 0.50 0.40 −0.31 0.47
MDM2-mWT 0.44 −0.14 −0.31 −0.05 0.25 0.34 −0.09 0.29
TERT-WT 0.02 0.10 −0.17 −0.26 −0.04 0.04 −0.22 0.01
TERT-DN −0.03 −0.10 −0.60 −0.15 0.51 0.18 −0.49 0.53
PTEN-WT 0.10 −0.04 −0.46 0.11 0.33 0.18 −0.18 0.37
PTEN-A3 −0.24 −0.07 −0.39 −0.06 0.20 0.04 −0.21 0.01
PTEN-G129R 0.39 0.04 −0.48 0.21 0.55 0.21 −0.17 0.30
Bcl-2 −0.14 −0.08 −0.39 0.02 0.09 0.21 −0.26 0.19
per2 −0.19 −0.44 −0.56 −0.01 0.50 0.36 −0.48 0.24
per3 −0.16 −0.28 −0.20 0.04 0.23 0.21 −0.26 0.10
Cyclin D1-11 0.21 0.32 0.43 −0.18 −0.36 −0.55 0.30 −0.28
STAT2-4 −0.10 −0.15 0.23 0.16 −0.07 0.23 0.13 −0.20
TSC1-4 −0.09 0.04 −0.29 0.40 0.03 0.34 0.02 0.43
Bad-22 0.04 −0.21 −0.13 0.16 0.27 0.19 −0.08 0.24
FAPP-4 0.34 −0.22 0.08 0.01 −0.05 −0.03 0.28 −0.05
FHO-6 −0.12 0.00 0.09 0.25 0.02 0.14 0.08 0.06
F25 + lactacystin −0.17 −0.09 −0.11 0.28 0.13 0.27 −0.07 0.39
F25 + ONO5046 −0.07 −0.07 0.14 0.37 −0.06 0.15 0.26 −0.01
F25 + CA-074 0.14 −0.01 0.20 0.43 −0.12 0.12 0.35 0.14
F25 + PQQ 0.03 0.10 0.40 0.52 −0.28 0.08 0.50 −0.03
F25 + PD98059 0.02 −0.56 −0.45 −0.08 0.61 0.45 −0.44 0.05
F25 + ALLN −0.37 −0.07 −0.27 −0.04 0.29 0.40 −0.44 0.23
F25 + ONO3403 −0.09 0.06 −0.22 0.40 0.11 0.31 −0.05 0.29
F25 + Y27632 0.23 −0.04 −0.17 0.36 0.42 0.34 −0.11 0.10
AMY1 Max MDM2-hmut MDM2-mWT TERT-WT TERT-DN PTEN-WT PTEN-A3
E2F-Low
FBRCA1-13
FMDM2hwt-6
p27-3
CAPN10-10
c-myc-1
MSSP-10
MM1
AMY1 1.00
Max 0.56 1.00
MDM2-hmut 0.54 0.46 1.00
MDM2-mWT 0.36 0.16 0.52 1.00
TERT-WT 0.30 0.37 0.02 0.32 1.00
TERT-DN 0.28 0.48 0.43 0.22 0.06 1.00
PTEN-WT 0.46 0.45 0.27 0.00 0.27 0.44 1.00
PTEN-A3 0.29 0.42 0.11 −0.14 −0.06 0.18 0.16 1.00
PTEN-G129R 0.48 0.48 0.43 0.36 0.09 0.54 0.55 0.18
Bcl-2 0.37 0.64 0.45 0.30 0.38 0.31 0.16 0.40
per2 0.49 0.37 0.29 −0.08 −0.10 0.42 0.32 0.36
per3 0.30 0.16 0.12 −0.19 −0.14 0.05 0.18 0.14
Cyclin D1-11 −0.25 0.19 −0.34 −0.25 −0.02 −0.06 −0.09 −0.07
STAT2-4 0.03 −0.02 −0.28 −0.14 0.06 −0.32 −0.09 −0.10
TSC1-4 0.21 0.15 0.31 −0.06 0.01 0.05 0.18 0.29
Bad-22 0.04 −0.01 0.28 −0.22 −0.21 0.16 0.06 −0.13
FAPP-4 0.10 −0.22 −0.31 0.13 0.07 −0.16 −0.11 −0.31
FHO-6 0.13 −0.02 0.13 −0.15 −0.17 −0.12 0.26 0.16
F25 + lactacystin 0.21 0.08 0.33 0.11 −0.06 0.14 0.13 −0.02
F25 + ONO5046 −0.18 −0.05 0.08 −0.10 −0.24 −0.28 −0.28 −0.16
F25 + CA-074 0.02 0.00 0.06 −0.15 −0.11 −0.41 −0.12 −0.24
F25 + PQQ −0.13 −0.06 −0.11 −0.24 −0.16 −0.62 −0.16 −0.15
F25 + PD98059 0.21 0.09 0.19 0.28 0.06 0.29 0.03 0.06
F25 + ALLN 0.03 −0.08 0.14 −0.02 0.01 0.27 0.12 0.29
F25 + ONO3403 0.28 0.20 0.55 0.11 0.00 0.08 0.20 0.32
F25 + Y27632 0.27 0.19 0.47 0.25 −0.25 0.13 −0.05 0.12
TABLE 14
PTEN-G129R Bcl-2 per2 per3 Cyclin D1- STAT2-4 TSC1-4 Bad-22 FAPP-4
PTEN-G129R 1.00
Bcl-2 0.04 1.00
per2 0.19 0.34 1.00
per3 0.10 0.05 0.78 1.00
Cyclin D1-11 0.04 −0.13 −0.17 0.04 1.00
STAT2-4 −0.28 0.05 0.13 0.30 0.16 1.00
TSC1-4 0.00 0.32 0.32 0.30 −0.42 0.01 1.00
Bad-22 0.18 −0.19 0.16 0.27 −0.13 −0.16 0.37 1.00
FAPP-4 −0.11 −0.16 −0.01 −0.09 0.02 0.28 −0.03 −0.01 1.00
FHO-6 0.03 −0.06 0.33 0.45 0.03 0.25 0.35 0.24 0.11
F25 + lactacystin 0.09 0.13 0.25 0.35 −0.13 0.15 0.37 0.32 −0.05
F25 + ONO5046 −0.29 0.14 −0.15 −0.01 −0.05 0.30 0.26 0.12 0.03
F25 + CA-074 −0.34 −0.01 −0.04 0.23 0.06 0.43 0.24 0.21 0.12
F25 + PQQ −0.30 −0.07 −0.20 0.09 0.11 0.44 0.14 0.08 0.12
F25 + PD98059 0.15 0.02 0.22 0.06 −0.21 0.15 −0.23 0.01 −0.02
F25 + ALLN −0.09 0.05 0.24 0.04 −0.55 −0.02 0.28 0.03 −0.22
F25 + ONO3403 0.03 0.35 0.17 0.14 −0.25 0.05 0.57 0.18 −0.32
F25 + Y27632 0.35 0.08 0.28 0.23 −0.01 0.04 0.07 0.12 −0.29
FHO-6 +lactacystin +ONO5046 + CA-074 F25 + PQQ PD98059 F25 + ALLN +ONO3403 +Y27632
PTEN-G129R
Bcl-2
per2
per3
Cyclin D1-11
STAT2-4
TSC1-4
Bad-22
FAPP-4
FHO-6 1.00
F25 + lactacystin 0.46 1.00
F25 + ONO5046 0.12 0.22 1.00
F25 + CA-074 0.20 0.24 0.62 1.00
F25 + PQQ 0.30 0.10 0.56 0.79 1.00
F25 + PD98059 −0.13 0.04 0.13 0.08 −0.17 1.00
F25 + ALLN 0.16 0.28 0.00 −0.13 −0.27 0.34 1.00
F25 + ONO3403 0.33 0.58 0.17 0.24 0.10 −0.07 0.29 1
F25 + Y27632 0.10 0.25 0.03 0.04 0.00 0.06 0.04 0.46 1
indicates data missing or illegible when filed
From the result of the Tables 3 to 14, there were identified 71 pairs of genes showing positive correlations (r>0.5) and 17 pairs of genes showing negative correlations (r<−0.5). A part of those gene combinations and functional relationship thereof is shown in Table 15.
TABLE 15
r values
1. Combinations of genes belonging to the same family
where correlation is naturally expected
Ha-ras v.s. Ki-ras 0.71
Ha-ras v.s. N-ras 0.56
Ki-ras v.s. N-ras 0.56
v-src v.s. erbB2 0.66
cystatin α v.s. cystatin E 0.54
PKCα-KN v.s. PKCε-KN 0.68
ERK-DN v.s. p38-DN 0.63
JNK-DN v.s. p38-DN 0.54
caspase-1 v.s. caspase-3 0.49
Hsdj v.s. DnaJ-61 0.40
2. Combination of a transcription factor and the target gene
p53 v.s. p21 0.56
3. Presence of a product at the downstream of the signal of
another product
Ha-las -> RhoA-DN −0.55
N-ras -> ERK-DN −0.51
Ras-DN -> Akt-DN 0.40
IKK-DN -> IkB-SR 0.75
PDGFR-Δ -> ERK-DN 0.62
CaMKIIα-active -> coup 0.56
p53 -> caspase-3 0.52
IkB-SR -> p53 0.52
IKK-DN -> p21 0.62
glucocorticoid-R -> STAT1 0.78
4. Protease and its substrate
m-calpain -> PDGFR-Δ 0.54
5. Simultaneous expression
p16 v.s. Bax 0.56
hsp90 v.s. caspase-3 0.63
JNK-DN v.s. μ-calpain 0.48
6. Binding protein
p53 v.s. MDM2-WT −0.56
p53 v.s. MDM2-mutated 0.62
hsp90 v.s. TERT-DN 0.53
As a result of the above method, there was constructed a gene function database where correlation among the genes having known functions was made clear. By referring to the database, it is now possible to easily elucidate the functions of the gene having unknown functions.
INDUSTRIAL APPLICABILITY As mentioned in details hereinabove, the invention of this application provides a novel method of analysis of functions of function-unknown genes useful as a genetic material for the Pharmacogenomics and for the manufacture of various useful proteins by means of genetic engineering and also provides a gene function database to be used for the analysis as well as a method for constructing the database.
